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FUNCTION Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the recruitment of ubiquitinated cargo proteins to autophagosomes via multiple domains that bridge proteins and organelles in different steps (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, PubMed:37802024). SQSTM1 first mediates the assembly and removal of ubiquitinated proteins by undergoing liquid-liquid phase separation upon binding to ubiquitinated proteins via its UBA domain, leading to the formation of insoluble cytoplasmic inclusions, known as p62 bodies (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). SQSTM1 then interacts with ATG8 family proteins on autophagosomes via its LIR motif, leading to p62 body recruitment to autophagosomes, followed by autophagic clearance of ubiquitinated proteins (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself degraded along with its ubiquitinated cargos (PubMed:16286508, PubMed:17580304, PubMed:37802024). Also required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex by sequestering the complex in inclusion bodies, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (PubMed:25101860). May regulate the activation of NFKB1 by TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, PubMed:19931284). May play a role in titin/TTN downstream signaling in muscle cells (PubMed:15802564). Adapter that mediates the interaction between TRAF6 and CYLD (By similarity).SUBUNIT Homooligomer or heterooligomer; may form homotypic arrays (PubMed:12887891, PubMed:19931284). Dimerization interferes with ubiquitin binding (PubMed:19931284). Component of a ternary complex with PAWR and PRKCZ (PubMed:11755531). Forms a complex with JUB/Ajuba, PRKCZ and TRAF6 (PubMed:15870274). Identified in a complex with TRAF6 and CYLD (By similarity). Identified in a heterotrimeric complex with ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the same ubiquitin molecule (PubMed:21923101). Interacts (via LIR motif) with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members, including GABARAP, GABARAPL1 and GABARAPL2; these interactions are necessary for the recruitment MAP1 LC3 family members to inclusion bodies containing polyubiquitinated protein aggregates and for their degradation by autophagy (PubMed:16286508, PubMed:17580304, PubMed:22421968, PubMed:24089205, PubMed:24668264). Interacts directly with PRKCI and PRKCZ (PubMed:10356400, PubMed:12813044, PubMed:12887891, PubMed:9566925). Interacts with EBI3, LCK, RASA1, NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5 (PubMed:10708586, PubMed:11244088, PubMed:12471037, PubMed:8551575, PubMed:8618896, PubMed:8650207, PubMed:8910285). Upon TNF stimulation, interacts with RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF-R1/TNFRSF1A, TRADD and RIPK1 (PubMed:10747026). Interacts with the proteasome subunits PSMD4 and PSMC2 (PubMed:15340068). Interacts with TRAF6 (PubMed:10747026). Interacts with 'Lys-63'-linked polyubiquitinated MAPT/TAU (PubMed:15953362). Interacts with FHOD3 (PubMed:21149568). Interacts with CYLD (PubMed:32185393). Interacts with SESN1 (PubMed:23274085). Interacts with SESN2 (PubMed:23274085, PubMed:25040165). Interacts with ULK1 (PubMed:25040165). Interacts with UBD (PubMed:25422469). Interacts with WDR81; the interaction is direct and regulates the interaction of SQSTM1 with ubiquitinated proteins (PubMed:28404643). Interacts with WDFY3; this interaction is required to recruit WDFY3 to cytoplasmic bodies and to PML bodies (PubMed:20168092). Interacts with LRRC25 (PubMed:29288164). Interacts with STING1; leading to relocalization of STING1 to autophagosomes (PubMed:29496741). Interacts (when phosphorylated at Ser-349) with KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering KEAP1 in inclusion bodies, promoting its degradation (PubMed:20452972, PubMed:20495340, PubMed:37306101). Interacts with MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester KEAP1 (PubMed:33393215). Interacts with GBP1 (By similarity). Interacts with TAX1BP1 (PubMed:34471133). Interacts with (ubiquitinated) PEX5; specifically binds PEX5 ubiquitinated at 'Lys-209' in response to reactive oxygen species (ROS) (PubMed:26344566). Interacts (via PB1 domain) with TNS2; the interaction leads to sequestration of TNS2 in cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and proteasomal degradation (PubMed:25101860). Interacts with IRS1; the interaction is disrupted by the presence of tensin TNS2 (PubMed:25101860). Interacts with TRIM5 (PubMed:20357094, PubMed:25127057). Interacts with TRIM11 (when ubiquitinated); promoting AIM2 recruitment to autophagosomes and autophagy-dependent degradation of AIM2 (PubMed:27498865). Interacts with TRIM13 (PubMed:22178386). Interacts with TRIM16 (PubMed:30143514). Interacts with TRIM23 (PubMed:28871090). Interacts with TRIM50 (PubMed:22792322). Interacts with TRIM55 (PubMed:15802564). Interacts with ECSIT; this interaction inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT complex (PubMed:31281713). Interacts with GABRR1, GABRR2 and GABRR3 (By similarity). Interacts with WDR83 (PubMed:38103557). Interacts with GRB2 (PubMed:35831301). Interacts with USP12; the interaction is independent of USP12 deubiquitinase activity and may be involved in regulation of autophagic flux (PubMed:30266909). Interacts with ASB6 (PubMed:34164402).INTERACTION In cardiac muscle, localizes to the sarcomeric band (By similarity). Localizes to cytoplasmic membraneless inclusion bodies, known as p62 bodies, containing polyubiquitinated protein aggregates (PubMed:11786419, PubMed:20357094, PubMed:22017874, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37306101, PubMed:37802024). In neurodegenerative diseases, detected in Lewy bodies in Parkinson disease, neurofibrillary tangles in Alzheimer disease, and HTT aggregates in Huntington disease (PubMed:15158159). In protein aggregate diseases of the liver, found in large amounts in Mallory bodies of alcoholic and nonalcoholic steatohepatitis, hyaline bodies in hepatocellular carcinoma, and in SERPINA1 aggregates (PubMed:11981755). Enriched in Rosenthal fibers of pilocytic astrocytoma (PubMed:11786419). In the cytoplasm, observed in both membrane-free ubiquitin-containing protein aggregates (sequestosomes) and membrane-surrounded autophagosomes (PubMed:15953362, PubMed:17580304). Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum (PubMed:22178386). Co-localizes with TRIM5 in cytoplasmic bodies (PubMed:20357094). When nuclear export is blocked by treatment with leptomycin B, accumulates in PML bodies (PubMed:20168092).ALTERNATIVE PRODUCTS Ubiquitously expressed.DEVELOPMENTAL STAGE During myogenesis, there is a marked increase in levels in fully differentiated myotubes compared to undifferentiated myoblasts.INDUCTION By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is directly activated by NFE2L2/NRF2; creating a positive feedback loop (PubMed:20452972).DOMAIN The UBA domain binds specifically 'Lys-63'-linked polyubiquitin chains of polyubiquitinated substrates (PubMed:12857745, PubMed:15340068, PubMed:28322253, PubMed:31857589). Mediates the interaction with TRIM55 (PubMed:15802564). Both the UBA and PB1 domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies (PubMed:15802564).DOMAIN The PB1 domain mediates homooligomerization and interactions with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81 (PubMed:12813044, PubMed:12887891, PubMed:15802564, PubMed:28404643). Both the PB1 and UBA domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies (PubMed:15802564).DOMAIN The ZZ-type zinc finger mediates the interaction with RIPK1.DOMAIN The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins.PTM Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer interface and increases binding affinity to ubiquitinated proteins (By similarity). Phosphorylation at Ser-407 also primes for subsequent phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing the affinity between the UBA domain and polyubiquitin chains (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1 is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by TBK1, leading to promote relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564).PTM Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 increases its ability to bind polyubiquitin chains by destabilizing the UBA dimer interface (PubMed:28322253). Deubiquitination by USP15 releases target vesicles for fast transport into the cell periphery (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, increasing SQSTM1 sequestering activity and promoting its degradation (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked polyubiquitination leading to xenophagic targeting of bacteria and inhibition of their replication (PubMed:27880896).PTM Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity by destabilizing the UBA dimer interface and increases binding affinity to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 (PubMed:31857589).PTM Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for efficient autophagic degradation of SQSTM1-cargo complexes by promoting affinity for ATG8 proteins and recruitment of p62 bodies to autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 by LYPLA1 (PubMed:37802024).PTM (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation (PubMed:24331465). Degradation by SpeB prevents autophagy, promoting to S.pyogenes intracellular replication (PubMed:24331465).PTM (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1-positive structures.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinated protein aggregates.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE A chromosomal aberration involving SQSTM1 is found in a form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) with NUP214.
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