Search results for RAE1

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Protein (1 results from a total of 1)

Identifier: R-HSA-157718
Species: Homo sapiens
Compartment: nuclear envelope
Primary external reference: UniProt: RAE1: P78406

Reaction (5 results from a total of 5)

Identifier: R-HSA-9708889
Species: Homo sapiens
Compartment: cytosol, nuclear envelope
Accessory protein ORF6 (6) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) exhibited strong inhibition on type I interferon (IFN)-responsive promoter activation in human embryonic kidney 293 (HEK293) cells that were transfected with either IFN-stimulated response element (ISRE) luciferase reporter plasmid and viral protein 6 expressing plasmid (Li JY et al. 2020; Yuen CK et al. 2020; Xia H et al. 2020; Miorin L et al. 2020). Fluorescence microscopy revealed that the expression of viral 6 (ORF6) protein blocked translocation of interferon regulatory factor 3 (IRF3) to the cell nucleus in poly(I:C)-induced human alveolar basal epithelial A549 cells (Xia H et al. 2020) and in Sendai virus (SeV)-induced HEK293 cells (Lei X et a. 2020; Yuen CK et al. 2020). The overexpression of ORF6 also blocked the nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2 in HEK293T cells and African green monkey kidney (Vero) cells (Xia H et al. 2020; Lei X et a. 2020; Miorin L et al. 2020). Upon activation, IRF3:IRF3, STAT1:STAT1 or STAT1:STAT2 dimers translocate into the nucleus by binding to the import receptor karyopherin (importin) alpha proteins such as KPNA1 which bind to nuclear localization signals (NLS) in cargo substrates. KPNA1 in turn interacts with karyopherin (importin) β‑1 (KPNB1), which mediates docking of NLS-containing cargo substrate bound to importin alpha subunit to the nuclear pore complex (NPC). SARS-CoV-2 6 (ORF6) was found to bind KPNA2 blocking IRF3 and STAT nuclear translocation (Xia H et al. 2020). In addition, viral ORF6 localized at NPC where it directly interacted with NUP98 and RAE1 in ORF6-expressing HEK293T cells (Miorin L et al. 2020; Addetia A et al. 2021; Kato K et al. 2021). Mass spectrometry-based proteomics further confirm the 6:NUP98:RAE1 complex formation (Gordon DE et al. 2020; Meyers JM et al. 2021). Orf6 binding to NUP98 is thought to impair docking of he NLS‑cargo:KPNA1:KPNB1 ternary complexes at the NPC (Miorin L et al. 2020). Similar findings were reported for SARS-CoV-1 ORF6 which inhibited IRF3-regulated interferon production (Kopecky-Bromberg SA et al. 2007) and antagonized STAT1 function (interferon signalling) by tethering the nuclear import factors KPNA2 and KPNB1 to the ER/Golgi membrane (Frieman M et al. 2007) or by impairing docking of cargo-receptor (karyopherin/importin) complex thus disrupting nuclear import (Miorin L et al. 2020).

In addition to blocking nuclear import of host proteins, targeting the NUP98:RAE complex by SARS-CoV-2 6 prevents host mRNA export through NPC (Addetia A et al. 2021; Kato K et al. 2021).

Identifier: R-HSA-9727293
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane, endoplasmic reticulum-Golgi intermediate compartment membrane
Protein 6 of SARS-Cov-2 has been shown in HEK 293 T cells to localize within 160 nm of nuclear pore complexes present at the nuclear envelope and at annulate lamellae in the cytoplasm, where it binds to the Nup98-Rae1 complex (Miorin et al, 2020).
Identifier: R-HSA-9768142
Species: Homo sapiens
Compartment: cytosol, nuclear envelope, nucleoplasm
Phosphorylation-induced dimerization and activation of interferon regulatory factor 3 (IRF3) or IRF7 results in the translocation of IRF3/IRF7 dimer from the cytosol into the nucleus.

SARS-CoV-2 6 (ORF6) interacts with importin KPNA2 and components of the nuclear pore complex, NUP98 and RAE1, to block nuclear translocation of transcription factors such as IRF3 (Xia H et al. 2020; Miorin L et al. 2020).

Identifier: R-HSA-9727292
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane, cytosol
SARS-Cov-2 mRNA6 open reading frame has a length of 186 nt and encodes the 61 aa protein 6 (Wu et al, 2020). Protein 6 has a membrane-embedded alpha-helix on its N-terminus and initially localizes to the ER and the membranes of autophagosomes and lysosomes, as shown in HEK 293 T cells (Lee et al, 2021).

Protein 6 of SARS-Cov-2 has been shown in HEK 293 T cells to localize within 160 nm of nuclear pore complexes present at the nuclear envelope and at annulate lamellae in the cytoplasm, where it binds to the Nup98-Rae1 complex (Miorin et al, 2020).
Identifier: R-HSA-9710963
Species: Homo sapiens
Compartment: cytosol
Upon viral infection, type I interferons (IFNs) (such as IFN-a/b) stimulate the transcription of antiviral interferon-stimulated genes (ISGs) by triggering phosphorylation, dimerization of signal transducer and activator of transcription 1 (STAT1) and STAT2, formation of interferon-stimulated gene factor 3 (ISGF3) complex with interferon regulatory factor 9 (IRF9), and nuclear translocation of of ISGF3 complex (Stark GR et al. 2012). STAT1 contains a nonclassical nuclear localization signal (NLS) sequence which is exposed only upon phosphorylation‑induced homo‑ or heterodimerization of STAT1 (Nardozzi J et al. 2010; Fagerlund R et al. 2002; McBride KM et al. 2002). In the cytoplasm, the nonclassical NLS of STAT1 dimers is initially recognized by an adaptor molecule, importin subunit α‑5 (also known as karyopherin subunit α‑1 or KPNA1) (McBride KM et al. 2002; Nardozzi J et al. 2010). KPNA1 then recruits importin β‑1 (karyopherin subunit β‑1 or KPNB1) via the N‑terminal importin β binding (IBB) domain of KPNA1 to form the NLS‑cargo:KPNA1:KPNB1 ternary complex (Cingolani G et al. 1999). The formed NLS‑cargo:KPNA1:KPNB1 complex is targeted to the nuclear pore complex (NPC) and then passes through nuclear pores via the interaction of KPNB1 with phenylalanine-glycine repeats (FG- repeats) (Moroianu J et al. 1995; McBride KM et al. 2002; Otsuka S et al. 2008; Chook  YM & Süel KE. 2011). Many viruses encode proteins that subvert nuclear transport of activated STAT1 to antagonize the IFN signaling pathway (Shen Q et al. 2021). For example, severe acute respiratory syndrome coronavirus type 1 (SARS‑CoV-1) encodes an accessory protein orf6 which is thought to block the nuclear import of STAT1 by binding and tethering KPNA2 and KPNB1 to the endoplasmic reticulum (ER)/Golgi intermediate compartment (ERGIC) thus limiting free KPNB1 in the cytoplasm and reducing the p-STAT1:KPNA1:KPNB1 complex formation (Frieman M et al. 2007). Similar findings were reported for SARS-CoV-2 orf6 which interacts with KPNA2 (Xia H et al. 2020) and blocks the nuclear import of STAT1 (Lei X et al. 2020). In addition, SARS-CoV-2 orf6 also blocks STAT1 nuclear translocation by interacting with the NUP98:RAE1 complex. This disrupts the interaction between NUP98 and the p-STAT1:KPNA1:KPNB1 complex, thus preventing the docking of this complex at the nuclear pore (Miorin L et al. 2020).

Complex (2 results from a total of 2)

Identifier: R-HSA-9631759
Species: Homo sapiens
Compartment: nuclear envelope
Identifier: R-HSA-9708891
Species: Homo sapiens
Compartment: nuclear envelope
SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with NUP98:RAE1 (Miorin L et al. 2020).

Pathway (1 results from a total of 1)

Identifier: R-HSA-9705671
Species: Homo sapiens
Coronaviruses (CoVs) are positive-sense RNA viruses that replicate in the interior of double membrane vesicles (DMV) in the cytoplasm of infected cells (Stertz S et al. 2007; Knoops K et al. 2008; V'kovski P et al. 2021). The viral replication and transcription are facilitated by virus-encoded non-structural proteins (SARS-CoV-2 nsp1–nsp16) that assemble to form a DMV-bound replication-transcription complex (RTC) (V'kovski P et al. 2021). The replication strategy of CoVs can generate both single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) species, that may act as pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptor (PRR) such as toll-like receptor 7 (TLR7) and TLR8, antiviral innate immune response receptor RIG-I (also known as DEAD box protein 58, DDX58) and interferon-induced helicase C domain-containing protein 1 (IFIH1, also known as MDA5) (Salvi V et al. 2021; Campbell GR et al. 2021; Rebendenne A et al. 2021). The activated PRRs trigger signaling pathways to produce type I and type III interferons IFNs and proinflammatory mediators that perform antiviral functions. This Reactome module describes the mechanisms underlying PRR-mediated sensing of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. First, endosomal recognition of viral ssRNA occurs by means of TLR7 and TLR8, which detect GU-rich ssRNA sequences (Salvi V et al. 2021; Campbell GR et al. 2021). Second, SARS-CoV-2 dsRNA replication intermediates can be recognized by cytoplasmic receptors DDX58 and IFIH1 which bind to mitochondrial antiviral-signaling protein (MAVS, IPS-1) to induce the IFN-mediated antiviral response (Rebendenne A et al. 2021; Yin X et al. 2021). In addition, SARS-CoV-2 E can be sensed by TLR2 (Zheng M et al. 2021). Further, cellular nucleic acid-binding protein (CNBP) and La-related protein 1 (LARP1) can directly bind SARS-CoV-2 gRNA to repress SARS-CoV-2 replication (Schmidt N et al. 2021). This module also describes several strategies developed by SARS-CoV-2 to evade or alter host immunity, including escaping innate immune sensors, inhibiting IFN production and signaling, and evading antiviral function of IFN stimulated gene (ISG) products. For example, SARS-CoV-2 encodes nsp14 and nsp16 which possess guanine-N7-methyltransferase activity and 2’-O-methyl-transferase activity respectively (Ogando NS et al. 2020; Krafcikova P et al. 2020; Viswanatha T et al. 2020; Lin S et al. 2021; Yan L et al. 2021). In human coronaviruses nsp14 generates 5' cap-0 viral RNA (m7GpppN, guanine N7-methylated) and nsp16 further methylates cap-0 viral RNA. These viral RNA modifications mimic the 5'-cap structure of host mRNAs allowing the virus to efficiently evade recognition by cytosolic DDX58 and IFIH1 (Chen Y et al. 2009, 2011; Daffis S et al. 2010, shown for CoVs such as SARS-CoV-1 and MERS-CoV). Structural studies and computational analysis suggest that properties and biological functions of SARS-CoV-2 nsp14 and nsp16 could be very similar to these of SARS-CoV-1 (Rosas-Lemus M et al. 2020; Lin S et al. 2020; Viswanathan T et al. 2020; Krafcikova P et al. 2020; Jiang Y et al. 2020; Wilamowski M et al. 2021). Further, the uridylate‐specific endoribonuclease (EndoU) activity of SARS-CoV-2 nsp15 degrades viral RNA to hide it from innate immune sensors (Frazier MN et al. 2021). Moreover, SARS-CoV-2 encodes several proteins that directly bind to host targets associated with SARS‑CoV‑2 infection and cytokine production (Shin D et al. 2020; Viswanathan T et al. 2020; Xia H et al. 2020; Matsuyama T et al. 2020; Yuen CK et al. 2020; reviewed by Park A & Iwasaki A 2020). This Reactome module describes several such binding events and their consequences. For example, as a deubiquitinating and deISGylating enzyme, viral nsp3 binds to and removes ISG15 from signaling proteins such as IRF3 and IFIH1 thereby modulating the formation of signaling complexes and the activation of IRF3/7 and NF-kappaB (Liu CQ et al. 2021). Binding of SARS-CoV-2 nsp6, nsp13 or membrane (M) protein to cytosolic TBK1 prevents IRF3/7 activation and inhibits IFN production downstream of DDX58, IFIH1, MAVS and STING signaling pathways (Xia H et al. 2020; Sui L et al. 2021). Next, M protein targets MAVS to prevent the formation of the MAVS signalosome complex and thereby inhibits downstream signaling pathways of DDX58 and IFIH1 (Fu YZ et al. 2021). Binding of SARS-CoV-2 nucleocapsid (N) protein to E3 ubiquitin ligase TRIM25 inhibits TRIM25-mediated DDX58 ubiquitination and the DDX58 signaling pathway (Gori SG et al. 2021). N interacts with NLRP3 to promote the assembly and activation of the NLRP3 inflammasome (Pan P et al. 2021). The interaction between viral N and MASP2 promotes MASP2-mediated cleavage of C4 (Ali YM et al. 2021) and C2 (Kang S et al. 2021) leading to the hyperactivation of the complement system. Besides, viral N promotes NF-kappaB activation by targeting signaling complexes of TAK1 and IKK (Wu Y et al. 2021). The ion channel activities of accessory protein ORF3a or 3a (open reading frame 3a) and SARS‑CoV‑2 envelope (E) protein contribute to activation of the NLRP3 inflammasome leading to highly inflammatory pyroptotic cell death (based on findings for SARS-CoV-1, Siu KL et al. 2019). SARS-CoV-2 nsp5 protease (3CLpro) cleaves TAB1, a component of the TAK1 complex, thus inhibiting NF-kappaB activation (Moustaqil M et al .2021). 3CLpro targets NLRP12 which modulates the expression of inflammatory cytokines through the regulation of the NFkappaB and MAPK pathways (Moustaqil M et al. 2021). SARS-CoV-2 6 (ORF6) interacts with importin KPNA2 and components of the nuclear pore complex, NUP98 and RAE1, to block nuclear translocation of IRF3, STAT1 and STAT2 (Xia H et al. 2020; Miorin L et al. 2020). SARS-CoV-2 9b (ORF9b) inhibits the MAVS-mediated production of type I IFNs by targeting TOMM70 on the mitochondria (Jiang HW et al. 2020). Binding of mitochondrial viral 9 to IKBKG prevents MAVS-dependent NF-kappaB activation (Wu J et al. 2021). Although the evasion mechanisms are mainly conserved between SARS-CoV-1 and SARS-CoV-2 (Gordon DE et al. 2020), studies identified SARS-CoV-2-specific modulations of host immune response that may contribute to pathophysiological determinants of COVID-19 (Gordon DE et al. 2020; Schiller HB et al. 2021). This Reactome module describes several virus-host interactions identified in cells during SARS-CoV-2, but not SARS-CoV-1, infection. For example, SARS-CoV-2 8 (ORF8) regulates the expression of class I MHC on the surface of the infected cells through an autophagy-dependent lysosomal degradation of class I MHC (Zhang Y et al. 2021). At the plasma membrane, binding of secreted viral 8 to IL17RA activates IL17 signaling pathway leading to an increased secretion of cytokines/chemokines thus contributing to cytokine storm during SARS-CoV-2 infection (Lin X et al. 2021). Furthermore, SARS-CoV-2-host interactome and proteomics studies identified various human proteins that are targeted by SARS-CoV-2 proteins (Gordon DE et al. 2020a, b; Bojkova D et al. 2020; Stukalov A et al. 2021; Li J et al. 2021; Messina F et al. 2021). This Reactome module does not cover all identified SARS-CoV-2–human interactions; the module describes those associations that were functionally validated.
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