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Pathway (30 results from a total of 44)

Identifier: R-HSA-9648002
Species: Homo sapiens
RAS proteins undergo several processing steps during maturation including farnesylation, carboxy-terminal cleavage and carboxymethylation, among others. These steps are required for their membrane localization and function and ultimately for their ability to activate RAF (reviewed in Gysin et al, 2011; Ahearn et al, 2018).
Identifier: R-HSA-69416
Species: Homo sapiens
Procaspase-8 monomers undergo dimerization. The dimerization event occurs at death-inducing signaling complex (DISC) and results in a reposition of the procaspase-8 inter-subunit linker to become accessible for intermolecular processing by the associated procaspase-8 molecule [Keller N et al 2010; Oberst A et al 2010].
Identifier: R-HSA-448706
Species: Homo sapiens
Compartment: cytosol
The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1α (IL1A), IL-1β (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough & Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology.
Identifier: R-HSA-167060
Species: Homo sapiens
All neurotrophins (NTs) are generated as pre-pro-neurotrophin precursors. The signal peptide is cleaved off as NT is associated with the endoplasmic reticulum (ER). The resulting pro-NT can form a homodimer spontaneously which then transits to the Golgi apparatus and then onto the trans-Golgi network (TGN). Resident protein convertases (PCs) can cleave off the pro-sequence and mature NT is is targeted to constitutively released vesicles. The pro-NT form can also be released to the extracellular region.
Identifier: R-HSA-264876
Species: Homo sapiens
Compartment: nucleoplasm, cytosol, endoplasmic reticulum membrane, endoplasmic reticulum lumen, COPII-coated ER to Golgi transport vesicle, Golgi lumen, secretory granule lumen, secretory granule membrane, plasma membrane, extracellular region
The generation of insulin-containing secretory granules from proinsulin in the lumen of the endoplasmic reticulum (ER) can be described in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yield insulin, translocation of the granules across the cytosol to the plasma membrane.
Transcription of the human insulin gene INS is activated by 4 important transcription factors: Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the promoters of the insulin gene and act synergistically to promote transcription. Expression of the transcription factors is upregulated in response to glucose.
The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is stabilized by glucose.
In the process annotated in detail here, within the ER, three intramolecular disulfide bonds form between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by Ero1-like alpha
The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7 and the proinsulin forms complexes with zinc and calcium.
Proinsulin-zinc-calcium complexes bud in vesicles from the trans-Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules the endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the cystine-bonded A and B chains of mature insulin and the C peptide, which will also be secreted with the insulin. The insulin-zinc-calcium complexes form insoluble crystals within the granule
The insulin-containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin-1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.
A pancreatic beta cell contains about 10000 insulin granules of which about 1000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE-type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin-2/VAMP2 on the granule membrane. Exocytosis is a calcium-dependent process due to interaction of the calcium-binding membrane protein Synaptotagmin V/IX with the SNARE-type proteins.
Identifier: R-HSA-72306
Species: Homo sapiens
Genes encoding transfer RNAs (tRNAs) are transcribed by RNA polymerase III in the nucleus and by mitochondrial RNA polymerase in the mitochondrion.
In the nucleus transcription reactions produce precursor tRNAs (pre-tRNAs) that have extra 5' leaders, 3' trailers, and, in some cases, introns which are removed by enzymes and enzyme complexes: RNase P cleaves the 5' leader, RNase Z cleaves the 3' trailer, TRNT1 polymerizes CCA onto the resulting 3' end, the TSEN complex cleaves at each end of the intron, and the tRNA ligase complex ligates the resulting exons (reviewed in Rossmanith et al. 1995, Phizicky and Hopper 2010, Suzuki et al. 2011, Abbott et al. 2014, Li and Mason 2014). The nucleotides within tRNAs undergo further chemical modifications such as methylation and deamination by a diverse set of enzymes (reviewed in Helm and Alfonzo 2014, Boschi-Muller and Motorin 2013). The order of events for each tRNA is not fully known and the understanding of the overall process is complicated by the retrograde (cytosol to nucleus) transport of tRNAs.
In the mitochondrial matrix transcription produces long precursor RNAs, H strand transcripts and an L strand transcript, that are cleaved by mitochondrial RNase P (an entirely proteinaceous complex), ELAC2, and other nucleases to yield 12S rRNA, 16S rRNA, mRNAs, and pre-tRNAs lacking 3' CCA sequences (reviewed in Van Haute et al. 2015). TRNT1 polymerizes an untemplated CCA sequence onto the 3' ends of the pre-tRNAs and chemical modifications are made to several nucleotides in the tRNAs.
Identifier: R-HSA-72312
Species: Homo sapiens
Each eukaryotic cytosolic ribosome contains 4 molecules of RNA: 28S rRNA (25S rRNA in yeast), 5.8S rRNA, and 5S rRNA in the 60S subunit and 18S rRNA in the 40S subunit. The 18S rRNA, 5.8S rRNA, and 28S rRNA are produced by endonucleolytic and exonucleolytic processing of a single 47S precursor (pre-rRNA) (reviewed in Henras et al. 2015). Transcription of ribosomal RNA genes, processing of pre-rRNA, and assembly of precursor 60S and 40S subunits occur in the nucleolus (reviewed in Hernandez-Verdun et al. 2010), with a few late reactions occurring in the cytosol. Within the nucleolus non-transcribed DNA and inactive polymerase complexes are located in the fibrillar center, active DNA polymerase I transcription occurs at the interface between the fibrillar center and the dense fibrillar component, early processing of pre-rRNA occurs in the dense fibrillar component, and late processing of pre-rRNA occurs in the granular component (Stanek et al. 2001).
Processed ribosomal RNA contains many modified nucleotides which are generated by enzymes acting on encoded nucleotides contained in the precursor rRNA (reviewed in Boschi-Muller and Motorin 2013). The most numerous modifications are pseudouridine residues and 2'-O-methylribonucleotides. Pseudouridylation is guided by base pairing between the precursor rRNA and a small nucleolar RNA (snoRNA) in a Box C/D snoRNP (reviewed in Henras et al 2004, Yu and Meier 2014). Similarly, 2'-O-methylation is guided by base pairing between the precursor rRNA and a snoRNA in a Box H/ACA snoRNP (reviewed in Henras et al. 2004, Hamma and Ferre-D'Amare 2010). Other modifications include N(1)-methylpseudouridine, 5-methylcytosine, 7-methylguanosine, 6-dimethyladenosine, and 4-acetylcytidine. Modification of nucleotides occur as the pre-rRNA is being cleaved. However, the order of cleavage and modification steps is not clear so these two processes are presented separately here. Defects in ribosome biogenesis factors can cause disease (reviewed in Freed et al. 2010).
Mitochondrial ribosomes are completely distinct from cytoplasmic ribosomes, having different protein subunits and 12S rRNA and 16S rRNA. The mitochondrial rRNAs are encoded in the mitochondrial genome and are produced by processing of a long H strand transcript. Specific residues in the rRNAs are modified by enzymes to yield 5 different types of modified nucleotides:
Identifier: R-HSA-8949664
Species: Homo sapiens
Proteolytic processing of proSMDT1 (proEMRE) regulates assembly of properly regulated mitochondrial calcium uniporter (MCU) complex (Konig et al. 2016). C2orf47 (MAIP) in a complex with AFG3L2 (m-AAA protease) binds the transit peptide of proSMDT1, promotes cleavage of the transit peptide by mitochondrial processing endopeptidase, and prevents proteolytic destruction of proSMDT1. SMDT1 that is not then incorporated with the regulatory subunits MICU1 and MICU2 (or MICU1 and MICU3 in neurons) into the MCU complex is degraded by AFG3L2, preventing assembly of unregulated MCU. Unprocessed proSMDT1 is proteolyzed by YME1L1.
Identifier: R-HSA-9036866
Species: Homo sapiens
Neurotrophins function as ligands for receptor tyrosine kinases of the NTRK (TRK) family, as well as the death receptor NGFR (p75NTR). While all four neurotrophins, NGF, BDNF, NTF3 (NT-3) and NTF4 (NT-4, NT-5, NTF5) can bind to and activate NGFR, they show different specificity for NTRKs. NGF exclusively activates NTRK1 (TRKA). BDNF and NTF4 are high affinity ligands for NTRK2 (TRKB). NTF3 is a high affinity ligand for NTRK3 (TRKC) and a low affinity ligand for NTRK2. Neurotrophins play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. For review, please refer to Lessmann et al. 2003, Chao 2003, and Park and Poo 2013.
Human NGF, also knowns as the nerve growth factor, is encoded by a gene on chromosome 1, which produces a single transcript. Nascent NGF protein, pre-pro-NGF, is 241 amino acids long. As pre-pro-NGF enters the endoplasmic reticulum (ER), the signal peptide, consisting of eighteen amino acids at the N-terminus, is cleaved, producing pro-NGF. Two molecules of pro-NGF form homodimers in the ER. After transport of pro-NGF homodimers to the Golgi, 103 amino acids at the N-terminus of pro-NGF are cleaved, producing mature NGF homodimers. Both pro-NGF homodimers and mature NGF homodimers are secreted to the extracellular space. Mature NGF homodimers activate NTRK1 signaling, while NGFR signaling can be activated by both mature and pro-NGF homodimers. Secreted pro-NGF homodimers may be cleaved by extracellular matrix proteases to produce mature NGF homodimers. For review, please refer to Poo 2001, Lu et al. 2005, Skaper et al. 2012, Bradshaw et al. 2015.
Human BDNF, also known as brain-derived neurotrophic factor, is encoded by a gene on chromosome 11, which, through the use of 9 alternative promoters and alternative splicing, produces 17 protein-coding transcripts. Most BDNF transcripts result in the same pre-pro-BDNF protein of 247 amino acids, but alternative promoters and different 5' and 3’UTRs allow to fine-tune regulation of BDNF expression at different developmental stages and at different levels of neuronal activity. Similar to NGF, pre-pro-BDNF is processed by proteolytic cleavage in the ER to produce pro-BDNF homodimers. It is unclear whether proteolytic processing of pro-BDNF, to produce mature BDNF homodimers, occurs in the Golgi or in the secretory granules. Extracellular matrix proteases can also cleave secreted pro-BDNF to produce mature BDNF homodimers. Secreted mature BDNF homodimers can activate NTRK2 signaling, while secreted pro-BDNF homodimers can activate NGFR signaling. For review, please refer to Poo 2001, Lu et al. 2005, Skaper et al. 2012, Park and Poo 2013.
Human NTF4, also known as neurotrophin-4, is transcribed from a gene on chromosome 19. A single experimentally confirmed transcript produces a pre-pro-NTF4 protein of 210 amino acids. After proteolytic processing in the ER and Golgi, mature NTF4 homodimers are secreted and can activate NTRK2 signaling (Hibbert et al. 2003). For review, please refer to Poo 2001, Skaper et al. 2012.
Human NTF3, also known as neurotrophin-3, is transcribed from a gene on chromosome 12. Two NTF3 transcripts have been experimentally confirmed, but only the longer NTF3 splice variant of 270 amino acids has been studied. After proteolytic processing in the ER and Golgi, mature NTF3 homodimers are secreted and can activate NTRK3 signaling (Seidah et al. 1996, Farhadi et al. 2000). For review, please refer to Poo 2001, Skaper et al. 2012.
Identifier: R-HSA-3215018
Species: Homo sapiens
Compartment: nucleoplasm
The initial translation products of SUMO1, SUMO2, and SUMO3 are precursors that have extra amino acid residues at the C-terminus (reviewed in Wang and Dasso 2009, Wilkinson and Henley 2010, Hannoun et al. 2010, Gareau and Lima 2010, Hay 2007). SUMO1 has 4 extra residues, SUMO2 has 2 extra residues, and SUMO3 has 11 extra residues. Proteolytic cleavage by SUMO peptidases (SENPs) removes the propeptide and leaves diglycine residues at the C-terminus. Each SENP has distinct preferences for certain SUMOs. SENP1 has highest activity on SUMO1; SENP2 and SENP5 have highest activity on SUMO2 (Shen et al. 2006, Reverter and Lima 2006, Mikolajczyk et al. 2007). SENP1 and SENP2 are predominantly nucleoplasmic (Bailey and O'Hare 2004, Kim et al. 2005, Zhang et al. 2002, Hang and Dasso 2002, Itahana et al. 2006) and SENP5 is predominantly nucleolar (Di Bacco et al. 2006, Gong and Yeh 2006), therefore the processing reactions are believed to occur in the nucleus. The processed SUMO is then activated by formation of a thioester bond with a cysteine residue of an E1 enzyme, UBA2 (SAE2) in a complex with SAE1. SUMO is then transferred from the E1 enzyme to an E2 enzyme, UBC9 (UBE2I).
Identifier: R-HSA-3065679
Species: Homo sapiens
Compartment: nucleoplasm
SUMO1, 2, and 3 are initially expressed as propeptides containing extra residues at the C-terminus. (SUMO1 has 4 residues, SUMO2 has 2 residues, and SUMO3 has 11 residues,) SENP1, 2, and 5 are endoproteases that process the precursors to produce the mature peptides (reviewed in Wang and Dasso 2009, Wilkinson and Henley 2010, Hannoun et al. 2010, Gareau and Lima 2010). SENP1 processes SUMO1 with greater efficiency than SUMO2 or SUMO3. SENP2 and SENP5 process SUMO2 with greater efficiency than SUMO1 or SUMO3 (Gong and Yeh 2006, Mikolajczyk et al. 2007). SENP1 shuttles between the cytosol and nuceoplasm and is predominantly nuclear (Bailey and O'hare 2004, Kim et al. 2005). SENP2 also shuttles (Itahana et al. 2006) and is mainly located on nucleoplasmic filaments of the nuclear pore complex (Hang and Dasso 2002, Zhang et al. 2002). SENP5 is located mostly in the nucleolus (Di Bacco et al. 2006, Gong and Yeh 2006).
Identifier: R-HSA-5689880
Species: Homo sapiens
Ub-specific processing proteases (USPs) are the largest of the DUB families with more than 50 members in humans. The USP catalytic domain varies considerably in size and consists of six conserved motifs with N- or C-terminal extensions and insertions occurring between the conserved motifs (Ye et al. 2009). Two highly conserved regions comprise the catalytic triad, the Cys-box (Cys) and His-box (His and Asp/Asn) (Nijman et al. 2005, Ye et al. 2009, Reyes-Turcu & Wilkinson 2009). They recognize their substrates by interactions of the variable regions with the substrate protein directly, or via scaffolds or adapters in multiprotein complexes.
Identifier: R-HSA-6784531
Species: Homo sapiens
Genes encoding transfer RNAs are transcribed in the nucleus by RNA polymerase III. (Distinct processes of transcription and processing also occur in mitochondria.) The initial transcripts, pre-tRNAs, contain extra nucleotides at the 5' end and 3' end. 6.3% (32 of 509) of human tRNAs also contain introns, which are located in the anticodon loop, 3' to the anticodon. The additional nucleotides are removed and a non-templated CCA sequence is added to the resulting 3' terminus by processing reactions in the nucleus and cytosol (reviewed in Nakanishi and Nureki 2005, Phizicky and Hopper 2010).
The order of processing and nucleotide modification events may be different for different tRNAs and its analysis is complicated by a retrograde transport mechanism that can import tRNAs from the cytosol back to the nucleus (retrograde movement, Shaheen and Hopper 2005, reviewed in Phizicky 2005). Generally, the 5' leader of the pre-tRNA is removed first by endonucleolytic cleavage by the RNase P ribonucleoprotein complex, which contains a catalytic RNA (RNA H1 in humans) and at least 10 protein subunits (reviewed in Jarrous 2002, Xiao et al. 2002, Jarrous and Gopalan 2010).
The 3' trailer is then removed by RNase Z activity, a single protein in humans (reviewed in Maraia and Lamichhane 2011). ELAC2 is a RNase Z found in both nucleus and mitochondria. ELAC1 is found in the cytosol and may also act as an RNase Z. Human tRNA genes do not encode the universal acceptor 3' terminus CCA, instead it is added post-transcriptionally by TRNT1, an unusual polymerase that requires no nucleic acid template (reviewed in Xiong and Steitz 2006, Hou 2010, Tomita and Yamashita 2014).
In humans introns are spliced from intron-containing tRNAs in the nucleus by a two step mechanism that is distinct from mRNA splicing (reviewed in Popow et al. 2012, Lopes et al. 2015). The TSEN complex first cleaves 5' and 3' to the intron, generating a 2'3' cyclic phosphate on the 5' exon and a 5' hydroxyl group on the 3' exon. These two ends are ligated by a complex containing at least 6 proteins in a single reaction that both hydrolyzes the 2' phosphate bond and joins the 3' phosphate to the 5' hydroxyl. (In yeast the ligation and the hydrolysis of the 2' phosphate are separate reactions. The splicing reactions in yeast occur in the cytosol at the mitochondrial outer membrane.)
Mature transfer RNAs contain a large number of modified nucleotide residues that are produced by post-transcriptional modification reactions (reviewed in Li and Mason 2014). Depending on the specific tRNA these reactions may occur before or after splicing and before or after export from the nucleus to the cytosol.
Identifier: R-HSA-6785470
Species: Homo sapiens
Each strand of the circular mitochondrial genome is transcribed to yield long polycistronic transcripts, the heavy strand transcript and the light strand transcript, which are then cleaved to yield tRNAs, rRNAs, and mRNAs (Mercer et al. 2011, reviewed in Suzuki et al. 2011, Rossmanith 2012, Powell et al. 2015). Mitochondrial RNase P, which is completely distinct from nuclear RNase P in having different protein subunits and no RNA component, cleaves at the 5' ends of tRNAs. RNase Z, an isoform of ELAC2 in mitochondria, cleaves at the 3' ends of tRNAs. (A different isoform of ELAC2 serves as RNase Z in the nucleus.) Unknown nucleases make additional cleavages near the 5' end of MT-CO3, the 5' end of CO1, the 5' end of CYB, and the 3' end of ND6. TRNT1 (CCA-adding enzyme) then post-transcriptionally polymerizes the universal acceptor sequence CCA onto the 3' ends of the cleaved tRNAs. In yeast, plants, and protozoa additional tRNAs encoded in the nucleus are imported into mitochondria from the cytosol (reviewed in Schneider 2011), however human mitochondria encode a complete complement of 22 tRNAs required for translation and tRNA import has not been observed in mammals. Mutations that affect mitochondrial tRNA processing cause human diseases that are generally characterized by abnormalities in energy-requiring tissues such as brain and muscle (reviewed in Suzuki et al. 2011, Sarin and Leidel 2014).
Identifier: R-HSA-8868766
Species: Homo sapiens
Mitochondrial ribosomes contain 16S rRNA (large subunit) and 12S rRNA (small subunit) that are encoded in the mitochondrial genome and produced by processing of a long H strand transcript (reviewed in Van Haute et al. 2015). Enzymes encoded in the nucleus and acting in the mitochondrial matrix modify 5 nucleotides in the 12S RNA and 4 nucleotides in the 16S rRNA (reviewed in Van Haute et al. 2015).
Identifier: R-HSA-72187
Species: Homo sapiens
Compartment: nucleoplasm
The 3' ends of eukaryotic mRNAs are generated by posttranscriptional processing of an extended primary transcript. For almost all RNAs, 3'-end processing consists of two steps: (i) the mRNA is first cleaved at a particular phosphodiester bond downstream of the coding sequence, (ii) the upstream fragment then receives a poly(A) tail of approximately 250 adenylate residues, whereas the downstream fragment is degraded. The two partial reactions are coupled so that reaction intermediates are usually undetectable. While 3' processing can be studied as an isolated event in vitro, it appears to be connected to transcription, splicing, and transcription termination in vivo.

The only known exception to the rule of cleavage followed by polyadenylation are the major histone mRNAs, which are cleaved but not polyadenylated.

Identifier: R-HSA-9659379
Species: Homo sapiens
In mammals, sounds are processed in the cochlea, a spiral-shaped organ in the inner ear (reviewed in Basch et al. 2016, Fettiplace 2017, Koppl and Manley 2019). Low frequency sounds are sensed at the distal end (apex) of the cochlea; high frequency sounds are sensed at the proximal end (base) of the cochlea (reviewed in Dallos 1992, Manley 2018). Sound vibrations are transmitted from the eardrum through the three bones of the inner ear (malleus, incus, stapes) and the oval window of the cochlea to the fluids within the cochlea. Within the organ of Corti in the cochlea there are 3 rows of outer hair cells (OHCs) on the external side of the tunnel of Corti and 1 row of inner hair cells (IHCs) on the internal side (Spoendlin 1967). Each IHC synapses with approximately 20 afferent myelinated type I spiral ganglion neurons and functions as a sensory receptor to convert the energy of sound waves to secretion of glutamate neurotransmitter. Multiple OHCs synapse with each unmyelinated type II afferent neuron and OHCs are also synapsed with efferent medial olivocochlear fibers (Spoendlin 1967). The primary function of OHCs, however, is amplification of organ of Corti motions in response to sound (Ryan and Dallos 1975). Amplification is produced by changes in receptor-potential driven cell length caused by changes in the conformation of the unusual membrane protein prestin (SLC26A5, Zheng et al. 2000).
IHCs and OHCs sense the sonic vibrations by deflection of stereocilia on their apical surfaces (reviewed in Fettiplace et al. 2017, McPherson 2018). The stereocilia are arranged in rows of increasing height, with a stereocilium of one row connected to a stereocilium of another row by a tip link composed of a CDH23 dimer on the taller stereocilium joined at its N-termini to the N-termini of a PCDH15 dimer on the shorter stereocilium. CDH23 is connected to the cytoskeleton of the taller stereocilium via MYO7A (MyoVIIa), USH1C (Harmonin), and USH1G (Sans) (reviewed in Peng et al. 2011, Cosgrove and Zallocchi 2014, Barr-Gillespie 2015, Fettiplace 2017, McGrath et al. 2017, Cunningham and Müller 2019, Ó Maoiléidigh and Ricci 2019, Velez-Ortega and Frolenkov 2019) while PCDH15 on the shorter stereocilium interacts with LHFPL5, an auxiliary subunit of the mechanoelectrical transduction channel (MET channel, also known as the mechanotransduction channel), which contains at least TMC1 or TMC2, TMIE, and the auxiliary subunits LHFPL5 and CIB2 (reviewed in Fettiplace 2016, Qiu and Müller 2018, Corey et al. 2019). Deflection of stereocilia in the direction that increases tension on the tip link causes depolarization of the cell by increasing the open probability of the MET channel, which then transports calcium and potassium into the hair cell according to the gradient of those ions between the scala media (containing endolymph at 154 mM K+ and <1 mM Ca2+) at the apex of the cell and the scala tympani (containing perilymph at 7 mM K+) at the base (reviewed in Fettiplace and Kim 2014). Similarly, compression of the tip link by deflection of the stereocilia in the opposite direction decreases the open probability of the MET channel and causes hyperpolarization of the cell.
Depolarization of IHCs causes opening of voltage-gated calcium channels arrayed in stripes on the basolateral membrane close to ribbon synapses formed between the IHC and the afferent fiber of a myelinated type I spiral ganglion neuron. This results in a localized increase in cytosolic calcium ions which interact with Otoferlin (OTOF) on glutamate-containing synaptic vesicles at the ribbon structure to activate exocytosis of glutamate into the synapse formed with the afferent neuron (reviewed in Wichmann 2015, Pangrsic and Vogl 2018). Ribbon synapses are distinguished by electron-dense ribbon structures projecting from the presynaptic membrane into the cytosol and comprising at least BASSOON, RIBEYE (an isoform of CTBP2), and PICCOLINO (an isoform of PICCOLO). The ribbon structures appear to transiently bind synaptic vesicles and facilitate resupply of synaptic vesicles at active zones to refill the pool of readily releasable vesicles (reviewed in Moser et al. 2006, Moser et al. 2020).
In contrast with IHCs, OHCs mainly function in sound amplification by decreasing up to about 4% in length in response to depolarization caused by opening of the MET channel and increasing in length in response to hyperpolarization caused by channel closing, resulting in alternating compression and decompression between the reticular lamina and the basilar membrane. The changes in the length of the OHC are caused by very rapid (microseconds), voltage-sensitive changes in the conformation of the membrane protein prestin (SLC26A5). Stereociliary ATP2B2 (PMCA2) extrudes calcium ions and basally located KCNQ4 extrudes potassium ions to repolarize the OHC.
OHCs are synapsed with efferent cholinergic medial olivocochlear fibers (reviewed in Fritzsch and Elliott 2017, Fuchs and Lauer 2019). Acetylcholine released at the synapse binds an unusual, nicotine-antagonized, nicotinic receptor comprising CHRNA9 and CHRNA10. Upon binding acetylcholine, CHRNA9:CHRNA10 transports calcium ions into the OHC. The calcium activates SK2 potassium channels (KCNN2) and BK potassium channels (KCNMA1:KCNMB1) which extrude potassium ions, hyperpolarize the OHC, and inhibit activation of the OHC.
Loud sounds can cause a temporary threshold shift (temporary loss of hearing) caused by damage to stereocilia and synapses or permanent threshold shift (permanent loss of hearing) caused by damage or death of hair cells and neurons (reviewed in Kurabi et al. 2017).
Identifier: R-HSA-69183
Species: Homo sapiens
Compartment: nucleoplasm
The key event that allows the processive synthesis on the lagging strand, is polymerase switching from pol alpha to pol delta, as on the leading strand. However, the processive synthesis on the lagging strand proceeds very differently. DNA synthesis is discontinuous, and involves the formation of short fragments called the Okazaki fragments. During the synthesis of Okazaki fragments, the RNA primer is folded into a single-stranded flap, which is removed by endonucleases. This is followed by the ligation of adjacent Okazaki fragments.
Identifier: R-HSA-1236975
Species: Homo sapiens
MHC class I molecules generally present peptide antigens derived from proteins synthesized by the cell itself to CD8+ T cells. However, in some circumstances, antigens from extracellular environment can be presented on MHC class I to stimulate CD8+ T cell immunity, a process termed cross-presentation (Rock & Shen. 2005). Cross-presentation/cross-priming is the ability of antigen presenting cells (APCs) to present exogenous antigens on MHC class I molecules to CD8+ T lymphocytes. Among all the APCs, Dendritic cells (DC) are the dominant antigen cross presenting cell types in vivo, although macrophages and B cells appear to cross present model antigens in vitro with a low degree of efficiency (Amigorena & Savina. 2010, Ackermann & Peter Cresswell. 2004). Compared to macrophages, DCs have low levels of lysosomal proteases and exhibit limited lysosomal degradation (Delamarre et al. 2005). This limited proteolysis of internalized antigens by DCs might contribute to their high efficiency for cross presentation (Monua & Trombetta. 2007). APCs acquire the exogenous antigens through endocytic mechanisms, especially phagosomes for particulate/cell-associated antigens and endosomes for soluble protein antigens. There does not seem to be a unique pathway for cross-presentation but rather different potential mechanisms of cross-presentation have been proposed. These proposed pathways can be classified according to the location where two key events occur: 1) processing of the antigenic protein and 2) loading of the processed peptide on to MHC I molecule (Blanchard & Shastri. 2010). Based on the requirement for TAP and cytosolic proteases two mechanisms have been described, a cytosolic pathway (TAP-dependent and proteasome-dependent) or a vacuolar pathway (TAP- and proteasome-independent) (Blanchard & Shastri. 2010, Amigorena & Savina. 2010). Regarding peptide-loading, MHC I could be loaded in the ER or in the phagosome and recycled to cell surface (Blanchard & Shastri. 2010). Exogenous soluble antigens are cross-presented by dendritic cells, albeit with lower efficiency than for particulate substrates. Soluble antigens destined for cross-presentation are taken up by distinct endocytosis mechanisms which route them into stable early endosomes and then to the cytoplasm for proteasomal degradation and peptide loading. The outcome of the cross presentation can be either tolerance or immunity (Rock & Shen. 2005).
Identifier: R-HSA-1679131
Species: Homo sapiens
Mammalian TLR3, TLR7, TLR8, TLR9 are endosomal receptors that sense nucleic acids that have been released from endocytosed/phagocytosed bacteria, viruses or parasites. These TLRs have a ligand-recognition domain that faces the lumen of the endosome (which is topologically equivalent to the outside of the cell), a transmembrane domain, and a signaling domain that faces the cytosol.

Under normal conditions, self nucleic acids are not recognized by TLRs due to multiple levels of regulation including receptor compartmentalization, trafficking and proteolytic processing (Barton GM et al 2006, Ewald SE et al 2008). At steady state TLR3, TLR7, TLR8, TLR9 reside primarily in the endoplasmic reticulum (ER), however, their activation by specific ligands only occurs within acidified endolysosomal compartments (Hacker H et al 1998, Funami K et al 2004, Gibbard RJ et al 2006). Several chaperon proteins associate with TLRs in the ER to provide efficient translocation to endolysosome. Upon reaching endolysosomal compartments the ectodomains of TLR7 and TLR9 are proteolytically cleaved by cysteine endoproteases. Both full-length and cleaved C-terminus of TLR9 bind CpG-oligodeoxynucleotides, however it has been proposed that only the processed receptor is functional.

Although similar cleavage of TLR3 has been reported by Ewald et al 2011, other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, thus TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).

There are no data on TLR8 processing, although the cell biology of TLR8 is probably similar to TLR9 and TLR7 (Gibbard RJ et al 2006, Wei T et al 2009).

Identifier: R-HSA-5610785
Species: Homo sapiens
In the absence of Hh signaling, the majority of full-length GLI3 is partially processed by the proteasome to a shorter form that serves as the principal repressor of Hh target genes (Wang et al, 2000). Processing depends on phosphorylation at 6 sites by PKA, which primes the protein for subsequent phosphorylation at adjacent sites by CK1 and GSK3. The hyperphosphorylated protein is then a direct target for betaTrCP-dependent ubiquitination and proteasome-dependent processing (Wang and Li, 2006; Tempe et al, 2006; Wen et al, 2010; Schrader et al, 2011; Pan and Wang, 2007).
Identifier: R-HSA-1912420
Species: Homo sapiens
Compartment: Golgi membrane, endoplasmic reticulum membrane, Golgi lumen, plasma membrane
NOTCH undergoes final posttranslational processing in the Golgi apparatus (Lardelli et al. 1994, Blaumueller et al. 1997, Weinmaster et al. 1991, Weinmaster et al. 1992, Uyttendaele et al. 1996). Movement of NOTCH precursors from the endoplasmic reticulum to Golgi is controlled by SEL1L protein, a homolog of C. elegans sel-1. SEL1L localizes to the endoplasmic reticulum membrane and prevents translocation of misfolded proteins, therefore serving as a quality control check (Li et al. 2010, Sundaram et al. 1993, Francisco et al. 2010). Similarly, C. elegans sel-9 and its mammalian homolog TMED2 are Golgi membrane proteins that participate in quality control of proteins transported from Golgi to the plasma membrane. Translocation of a mutant C. elegans NOTCH homolog lin-12 from the Golgi to the plasma membrane is negatively regulated by sel-9 (Wen et al. 1999). A GTPase RAB6 positively controls NOTCH trafficking through Golgi (Purcell et al. 1999).


Processing of mammalian NOTCH precursors in the Golgi typically involves the cleavage by FURIN convertase. Pre-NOTCH is a ~300 kDa protein, and cleavage by FURIN produces two fragments with approximate sizes of 110 kDa and 180 kDa. The 110 kDa fragment contains the transmembrane and intracellular domains of NOTCH and is known as NTM or NTMICD. The 189 kDa fragment contains NOTCH extracellular sequence and is known as NEC or NECD. The NTM and NEC fragments heterodimerize (Blaumueller et al. 1997, Logeat et al. 1998, Chan et al. 1998) and are held together by disulfide bonds and calcium ions (Rand et al. 2000, Gordon et al. 2009).


An optional step in Pre-NOTCH processing in the Golgi is modification by fringe enzymes. Fringe enzymes are glycosyl transferases that initiate elongation of O-linked fucose on fucosylated peptides by addition of a beta 1,3 N-acetylglucosaminyl group, resulting in formation of disaccharide chains on NOTCH EGF repeats (GlcNAc-bet1,3-fucitol). Three fringe enzymes are known in mammals: LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). LFNG shows the highest catalytic activity in modifying NOTCH (Bruckner et al. 2000, Moloney et al. 2000). Fringe-created disaccharide chains on NOTCH EGF repeats are further extended by B4GALT1 (beta-1,4-galactosyltransferase 1), which adds galactose to the N-acetylglucosaminyl group, resulting in formation of trisaccharide Gal-beta1,4-GlcNAc-beta1,3-fucitol chains (Moloney et al. 2000, Chen et al. 2001). Formation of trisaccharide chains is the minimum requirement for fringe-mediated modulation of NOTCH signaling, although fringe-modified NOTCH expressed on the cell surface predominantly contains tetrasaccharide chains on EGF repeats. The tetrasaccharide chains are formed by sialyltransferase(s) that add sialic acid to galactose, resulting in formation of Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). Three known Golgi membrane sialyltransferases could be performing this function: ST3GAL3, ST3GAL4 and ST3GAL6 (Harduin-Lepers et al. 2001). The modification of NOTCH by fringe enzymes modulates NOTCH-signaling by increasing the affinity of NOTCH receptors for delta-like ligands, DLL1 and DLL4, while decreasing affinity for jagged ligands, JAG1 and JAG2.
Identifier: R-HSA-1912422
Species: Homo sapiens
Compartment: nucleoplasm, cytosol, endoplasmic reticulum membrane, endoplasmic reticulum lumen, Golgi membrane, Golgi lumen, plasma membrane
In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009).

The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).

In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
Identifier: R-HSA-174414
Species: Homo sapiens
Compartment: nucleoplasm
Once polymerase switching from pol alpha to pol delta is complete the processive synthesis of a short run of DNA called an Okazaki fragment begins. DNA synthesis is discontinuous and as the extending Okazaki fragment reaches the RNA primer, this primer is folded into a single-stranded flap, which is removed by endonucleases. The process of extension is completed by the ligation of adjacent Okazaki fragments.
Identifier: R-HSA-171286
Species: Homo sapiens
The two viral membrane proteins, Env and the accessory protein Vpu, which are encoded by the same mRNA, are translated on the rough ER. All virion components need to traffic from their point of synthesis to sites of assembly on the plasma membrane. Env is an integral membrane protein. It is inserted cotranslationally into ER membranes and then travels through the cellular secretory pathway where it is glycosylated, assembled into trimeric complexes, processed into the gp41 and gp120 subunits by the cellular protease furin.
Identifier: R-HSA-9656256
Species: Homo sapiens
The majority of OGG1 mutants have been tested for their ability to excise 8-oxoguanine (8oxoG) from damaged DNA, while a small number of mutants have been tested for the ability to remove FapyG from DNA.
The following OGG1 mutants show at least a partial loss of their ability to remove 8oxoG:
OGG1 R46Q (Audebert, Chevillard et al. 2000; Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000, Bruner et al. 2000);
OGG1 R131Q (Chevillard et al. 1998, Bruner et al. 2000, Anderson and Dagget 2009);
OGG1 R229Q (Hyun et al. 2000, Hyun et al. 2002, Hill and Evans 2007);
OGG1 P266fs139* (Mao et al. 2007).
OGG1 R46L and OGG1 R131G have not been functionally studied but have been reported in cancer and predicted to be pathogenic. They are annotated as candidate disease variants based on their similarity with OGG1 R46Q and OGG1 R131Q, respectively.
OGG1 S326C, a frequent variant in European and Asian populations, is susceptible to oxidation, which diminishes catalytic activity under conditions of oxidative stress (Dherin et al. 1999, Yamane et al. 2004, Kershaw and Hodges 2012, Moritz et al. 2014).
The following OGG1 mutants show at least a partial loss of their ability to remove FapyG:
OGG1 R46Q (Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000).
OGG1 R46L has not been functionally studied but has been reported in cancer and predicted to be pathogenic. It is annotated as a candidate disease variant for FapyG excision, based on its similarity with OGG1 R46Q.
Identifier: R-HSA-9608290
Species: Homo sapiens
Compartment: nucleoplasm
MUTYH disease variants underlying the MUTYH-associated polyposis (MAP), also known as familial adenomatous polyposis 2 (FAP2), show impaired catalytic activity with respect to cleaving adenine mispaired with 8-oxoguanine (OGUA:Ade, also known as 8-oxoG:A). For some of the mutants, defective substrate processing is further aggravated by reduced substrate binding. MUTYH alpha-3 isoform (MUTYH-3) mutants and MUTYH gamma-3 isoform (MUTYH-6) mutants with experimentally demonstrated deficiency in catalytic activity include missense mutants MUTYH-3 Y165C (MUTYH-6 Y151C), MUTYH-3 R171W, MUTYH-3 R227W, MUTYH-3 R231H, MUTYH-3 R231L, MUTYH-3 V232F, MUTYH-3 R260Q, MUTYH-3 G272E, MUTYH-3 P281L, MUTYH-3 P391L (MUTYH-6 P377L), MUTYH-3 Q324H, MUTYH-3 Q324R,, MUTYH-3 A359V, MUTYH-3 G382D (MUTYH-6 G368D), MUTYH-3 A459D, MUTYH-6 R154H, MUTYH-6 I195V, MUTYH-6 M255V and MUTYH-3 L360P, in-frame indel mutants MUTYH-3 W138_M139insIW (also known as MUTYH 137insIW) and MUTYH-3 E466del (MUTYH-6 E452del), and frameshift mutants MUTYH-3 Y90fs*, MUTYH-3 Q377fs*, MUTYH-3 E466fs* and MUTYH-3 A368fs26* (commonly known as MUTYH 1103delC) (Jones et al. 2002, Chmiel et al. 2003, Wooden et al. 2004, Parker et al. 2005, Bai et al. 2005, Alhopuro et al. 2005, Bai et al. 2007, Ali et al. 2008, Yanaru-Fujisawa et al. 2008, Kundu et al. 2009, Forsbring et al. 2009, Molatore et al. 2010, D'Agostino et al. 2010, Goto et al. 2010, Raetz et al. 2012, Shinmura et al. 2012).
Identifier: R-HSA-9630221
Species: Homo sapiens
Compartment: nucleoplasm
NTHL1 D239Y is produced as a consequence of a single nucleotide polymorphism (SNP) rs3087468 in the NTHL1 gene. The frequency of this polymorphism varies in different populations. Substitution of aspartic acid residue at position 239 with tyrosine results in an NTHL1 protein that is still able to bind to damaged DNA but appears to have impaired glycosylase activity. Expression of NTHL1 D239Y in non-transformed human and mouse mammary epithelial cells increases genomic instability and leads to neoplastic transformation, acting as a dominant negative for wild-type NTHL1, through competition for substrate binding (Galick et al. 2013). It is uncertain if heterozygosity for NTHL1 D239Y polymorphism increases predisposition to cancer.
Identifier: R-HSA-8868773
Species: Homo sapiens
Each eukaryotic cytosolic ribosome contains 4 molecules of RNA: 28S rRNA (25S rRNA in yeast), 5.8S rRNA, and 5S rRNA in the 60S subunit and 18S rRNA in the 40S subunit. The 18S rRNA, 5.8S rRNA, and 28S rRNA are produced by endonucleolytic and exonucleolytic processing of a single 47S precursor (pre-rRNA) (reviewed in Henras et al. 2015). Transcription of ribosomal RNA genes, processing of pre-rRNA, modification of nucleotide residues within the rRNA, and assembly of precursor 60S and 40S subunits occur predominantly in the nucleolus (reviewed in Hernandez-Verdun et al. 2010, Boschi-Muller and Motorin 2013), with a few late reactions occurring in the cytosol.
Identifier: R-HSA-77595
Species: Homo sapiens
Compartment: nucleoplasm
The 3' ends of eukaryotic mRNAs are generated by posttranscriptional processing of an extended primary transcript. For almost all RNAs, 3' processing consists of two steps: The mRNA is first cleaved at a particular phosphodiester bond downstream of the coding sequence. The upstream fragment then receives a poly(A) tail of approximately 250 adenylate residues whereas the downstream fragment is degraded. The two partial reactions are coupled so that reaction intermediates are usually undetectable. While 3' processing can be studied as an isolated event in vitro, it appears to be connected to transcription, splicing and transcription termination in vivo.
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