SQSTM1

This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

Sequestosome 1

Autophagy receptor required for selective macroautophagy (aggrephagy). Functions as a bridge between polyubiquitinated cargo and autophagosomes. Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family (PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177).
Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:24128730, PubMed:20168092).
May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity).
May be involved in cell differentiation, apoptosis, immune response and regulation of K+ channels. 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).
Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741).
Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357, PubMed:33393215).

AggrephagyManual Assertion Based On ExperimentIPI:UniProtKB
Apoptotic processIEA:UniProtKB-KW
AutophagyManual Assertion Based On ExperimentIDA:UniProtKB
Autophagy of mitochondrion1 PublicationNAS:ParkinsonsUK-UCL
Brown fat cell proliferationIEA:Ensembl
Cell differentiationIEA:UniProtKB-KW
Endosomal transportManual Assertion Based On ExperimentTAS:UniProtKB
Endosome organizationManual Assertion Based On ExperimentIDA:UniProtKB
Energy homeostasisIEA:Ensembl
Immune system processIEA:UniProtKB-KW
Intracellular signal transductionManual Assertion Based On ExperimentTAS:UniProtKB
MacroautophagyManual Assertion Based On ExperimentIMP:GO_Central
MitophagyManual Assertion Based On ExperimentIGI:ParkinsonsUK-UCL
Negative regulation of protein ubiquitinationManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of transcription by RNA polymerase IIIEA:Ensembl
Positive regulation of apoptotic processTAS:Reactome
Positive regulation of long-term synaptic potentiationISS:ARUK-UCL
Positive regulation of protein localization to plasma membraneISS:ARUK-UCL
Positive regulation of protein phosphorylationIEA:Ensembl
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentTAS:UniProtKB
Protein import into nucleusIEA:Ensembl
Protein localizationManual Assertion Based On ExperimentTAS:UniProtKB
Protein localization to perinuclear region of cytoplasmManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of mitochondrion organization1 PublicationNAS:ParkinsonsUK-UCL
Regulation of protein complex stabilityManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of Ras protein signal transduction1 PublicationNAS:UniProtKB
Response to ischemiaIEA:Ensembl
Response to mitochondrial depolarisationManual Assertion Based On ExperimentIGI:ParkinsonsUK-UCL
Selective autophagyManual Assertion Based On ExperimentIMP:UniProtKB
Temperature homeostasisIEA:Ensembl
Ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentTAS:ProtInc

Cytoplasm, cytosol
Late endosome
Lysosome
Cytoplasmic vesicle, autophagosome
Nucleus
Endoplasmic reticulum
Nucleus, PML body
Cytoplasm, myofibril, sarcomere
In cardiac muscle, localizes to the sarcomeric band (By similarity).
Commonly found in inclusion bodies containing polyubiquitinated protein aggregates. In neurodegenerative diseases, detected in Lewy bodies in Parkinson disease, neurofibrillary tangles in Alzheimer disease, and HTT aggregates in Huntington disease. 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. Enriched in Rosenthal fibers of pilocytic astrocytoma. In the cytoplasm, observed in both membrane-free ubiquitin-containing protein aggregates (sequestosomes) and membrane-surrounded autophagosomes. Colocalizes with TRIM13 in the perinuclear endoplasmic reticulum. Co-localizes with TRIM5 in cytoplasmic bodies. When nuclear export is blocked by treatment with leptomycin B, accumulates in PML bodies.

Paget disease of bone 3 (PDB3):
A disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (FTDALS3):
A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Some FTDALS3 patients may also develop Paget disease of bone.
Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (NADGP):
A neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. Disease onset is in childhood or adolescence. NADGP transmission pattern is consistent with autosomal recessive inheritance.
Myopathy, distal, with rimmed vacuoles (DMRV):
An autosomal dominant myopathy with adult onset, characterized by muscle weakness of the distal upper and lower limbs, walking difficulties, and proximal weakness of the shoulder girdle muscles. Muscle biopsy shows rimmed vacuoles.

Phosphorylated. May be phosphorylated by PRKCZ (By similarity).
Phosphorylated in vitro by TTN (PubMed:15802564).
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 MTOR promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (By similarity).By Similarity3 Publications
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).
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).