Search results for PDCD6IP

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Protein (1 results from a total of 1)

Identifier: R-HSA-917717
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PDCD6IP: Q8WUM4

Reaction (4 results from a total of 4)

Identifier: R-HSA-9688832
Species: Homo sapiens
Compartment: cytosol
Upon necroptosis, receptor-interacting serine/threonine protein kinase 3 (RIPK3) phosphorylates the mixed lineage kinase domain-like (MLKL) protein at Thr357 and Ser358 located in the activation loop of pseudokinase domain. The RIPK3-mediated phosphorylation relieves the inhibitory effect of the pseudokinase domain of MLKL, thus allowing the activated MLKL to oligomerize and translocate from the cytosol to cell membranes to cause membrane disintegration. Various studies showed that the endosomal sorting complexes required for transport (ESCRT) pathway can remove phosphorylated MLKL-containing membrane vesicles from cells undergoing necroptosis, thereby attenuating the cell death process (Gong YN et al. 2017; Yoon S et al. 2017; Fan W et al. 2019). The ESCRT-associated proteins, programmed cell death 6-interacting protein (PDCD6IP or ALG-2-interacting protein X, ALIX) and syntenin-1 (SDCBP), were found to mediate exocytosis of MLKL antagonizing MLKL-mediated plasma membrane alteration (Fan W et al. 2019). Protein cross-linking followed by affinity purification assays detected PDCD6IP and SDCBP in immunoprecipitates of membrane-localized MLKL isolated from human HT-29 colon cancer cells expressing a 3xFlag-HA (hemagglutinin)-tagged MLKL (Fan W et al. 2019). Knockdown of either PDCD6IP or SDCBP reduced the levels of phospho-MLKL in the exosome fractions collected from the culture medium of caspase inhibitor z-VAD-fmk-treated HT-29 cells, suggesting that phosphorylated MLKL was eventually removed from membranes through PDCD6IP:SDCBP-mediated exocytosis. Mass spectrometry and immunoblotting showed that MLKL was associated with some components of ESCRT system within extracellular vesicles (EVs) released from caspase inhibitor z-VAD-fmk-treated HT-29 cells (Yoon S et al. 2017). Further, PDCD6IP was shown to bind tumor susceptibility gene 101 (TSG101 also known as VPS23, vacuolar protein sorting 23), the ESCRT-I subunit protein (von Schwedler UK et al. 2003; Okumura M et al. 2009). Knockdown of TSG101 prevented the exocytosis of phosphorylated MLKL in HT-29 cells, further confirming that mediated exocytosis of phospho-MLKL depends on the ESCRT pathway (Fan W et al. 2019).

SDCBP (syntenin-1) interacts directly with PDCD6IP (ALIX) through three LYPX(n)L motifs located in its N-terminus and with the conserved cytoplasmic domains of the syndecans, via its PDZ domains (Baietti MF et al. 2012). Syndecans are a family of proteins that by virtue of their extracellular heparan sulfate chains interact with a plethora of signaling and adhesion molecules (Sarrazin S et al. 2011). Since PDCD6IP binds several ESCRT proteins, PDCD6IP:SDCBP adapts syndecans and syndecan cargo to the ESCRT budding machinery, playing a role in membrane budding and scission at the endosome and generating intraluminal vesicles (ILVs) that are released as exosomes when multivesicular endosomes fuse with the plasma membrane (Baietti MF et al. 2012 ). Exocytosis was proposed to counteract the effector phase of necroptosis via ESCRT-, PDCD6IP:SDCBP- or RAB27A/B-mediated expulsion of MLKL-containing bubbles to diminish the MLKL residing at the plasma membrane (Gong YN et al. 2017; Yoon S et al. 2017; Fan W et al. 2019). However, the other study suggests that membrane bubbling during necroptosis is an incredibly dynamic and heterogenous phenomenon with protrusions variously extending, retracting and shedding in a fashion seemingly independent of the primary sites of MLKL accumulation and membrane damage (Samson AL et al. 2020).

Identifier: R-HSA-5210943
Species: Homo sapiens
Compartment: endosome membrane, cytosol
Through the action of vacuolar ATPase the pH of the target cell early endosome is lowered. In this environment, paga (PA63, Anthrax protective antigen, large fragment) dissociates from its receptor and forms an oligomeric channel in the endosome membrane through which the anthrax cya (EF, edema factor) and lef (LF, lethal factor) pass (Milne et al. 1994). Entry of cya and lef into the target cell cytosol is thought to be mediated by back fusion of intraluminal vesicles with the late endosomal membrane and to be positively regulated by PDCD6IP / ALIX protein (Abrami et al. 2004).
Identifier: R-HSA-5210947
Species: Homo sapiens
Compartment: endosome membrane, cytosol
Through the action of vacuolar ATPase the pH of the target cell early endosome is lowered. In this environment, pagA (197-794) (PA63, Anthrax protective antigen, large fragment) dissociates from its receptor and forms an oligomeric channel in the endosome membrane through which the anthrax cya (EF, edema factor) and lef (LF, lethal factor) pass (Milne et al. 1994). Entry of cya and lef into the target cell cytosol is thought to be mediated by back fusion of intraluminal vesicles with the late endosomal membrane and to be positively regulated by PDCD6IP / ALIX protein (Abrami et al. 2004).
Identifier: R-HSA-5620975
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Activated by phosphorylation, mixed lineage kinase domain-like protein (MLKL) was found to translocate to the plasma membrane, where MLKL interacts with phosphatidylinositol phosphates (PIPs) via a patch of positively charged amino acids at the surface of a four-helical bundle domain (4HBD) located in its N-terminal region (Dondelinger Y et al. 2014; Wang H et al. 2014; Hildebrand JM et al. 2014; Su L et al. 2014; Quarato G et al. 2016). Interfering with the formation of PI(5)P or PI(4,5)P2 using PIP binders such as PIKfyve (P5i) efficiently inhibited TNF-induced necroptosis in both mouse L929 and the human FADD-null Jurkat cells (Dondelinger Y et al. 2014). In vitro liposome experiments revealed that MLKL induces leakage of PIP- or cardiolipin-containing liposomes suggesting that MLKL may have pore-forming capacities to mediate cell death by membrane's permeabilizing (Dondelinger Y et al. 2014; Wang H et al. 2014; Tanzer MC et al. 2016; Petrie EJ et al. 2018). Liposome permeabilization assays demonstrated that the N-terminal 4HB domain of MLKL compromised membrane integrity, and was more effective on liposomes whose composition resembled that of plasma membranes than on those mimicking mitochondrial membranes (Tanzer MC et al. 2016). One study has proposed the 4HB domain might reorganize in membranes to assemble into ion channels (Xia B et al. 2016); however, this remains to be fully explored in cellular contexts and structurally. Other studies implicated MLKL in engaging mitochondrial membranes to provoke mitochondrial fission or promote ion channel activity (Cai Z et al. 2014), although subsequent studies have discounted these possibilities (Murphy JM et al. 2013; Tait SW et al. 2013; Moujalled DM et al. 2014; Wang H et al. 2014; reviewd by Murphy JM 2020). Studies in human cell lines suggest that upon induction of necroptosis MLKL shifts to the plasma membrane and membranous organelles such as mitochondria, lysosome, endosome and ER (Wang H et al. 2014), but MLKL trafficking via a Golgi-microtubule-actin-dependent mechanism facilitates plasma membrane accumulation of MLKL, where membrane disruption causes death (Samson AL et al. 2020). Based on studies showing that the 4HB domain can permeabilize membranes in vitro (Dondelinger Y et al. 2014; Su L et al. 2014; Wang H et al. 2014; Tanzer MC et al. 2016; Petrie EJ et al. 2018), it is thought that MLKL kills cells via direct action on the plasma membrane (Murphy JM 2020).

Various studies showed that the endosomal sorting complexes required for transport (ESCRT) pathway can remove phosphorylated MLKL-containing membrane vesicles from cells undergoing necroptosis, thereby attenuating the cell death process (Gong YN et al. 2017; Yoon S et al. 2017; Zargarian S et al. 2017; Fan W et al. 2019). The ESCRT-associated proteins, programmed cell death 6-interacting protein (PDCD6IP or ALG-2-interacting protein X, ALIX) and syntenin-1 (SDCBP), were found to antagonize MLKL-mediated plasma membrane alteration (Fan W et al. 2019). In addition, flotillin-mediated endocytosis was proposed to suppress necroptosis by removing MLKL from the plasma membrane and redirecting it for lysosomal degradation (Fan W et al. 2019).

Icon (1 results from a total of 1)

Species: Homo sapiens
Curator: Marc Gillespie
Designer: Cristoffer Sevilla
PDCD6IP icon
Programmed cell death 6-interacting protein
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