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-alpha, 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). |
---|
Cellular Location | Cytoplasmic vesicle, autophagosome. Preautophagosomal structure. Cytoplasm, cytosol. Nucleus, PML body. Late endosome. Lysosome. Nucleus Endoplasmic reticulum. Cytoplasm, myofibril, sarcomere {ECO:0000250|UniProtKB:O08623}. Note=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) {ECO:0000250|UniProtKB:O08623, ECO:0000269|PubMed:11786419, ECO:0000269|PubMed:11981755, ECO:0000269|PubMed:15158159, ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:17580304, ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20357094, ECO:0000269|PubMed:22017874, ECO:0000269|PubMed:22178386, ECO:0000269|PubMed:29343546, ECO:0000269|PubMed:29507397, ECO:0000269|PubMed:31857589, ECO:0000269|PubMed:37306101, ECO:0000269|PubMed:37802024} |
---|