UniProt functional annotation for Q9UMX0



	UniProt functional annotation for Q9UMX0

UniProt code: Q9UMX0.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin- proteasome system (UPS), autophagy and endoplasmic reticulum-associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome (PubMed:15147878). Plays a role in the ERAD pathway via its interaction with ER-localized proteins UBXN4, VCP and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:19822669, PubMed:18307982). Isoform 1, isoform 2 and isoform 3 play a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress (PubMed:18953672). Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy- related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:19148225, PubMed:20529957, PubMed:23459205). Negatively regulates the TICAM1/TRIF-dependent toll-like receptor signaling pathway by decreasing the abundance of TICAM1 via the autophagic pathway (PubMed:21695056). Isoform 1 and isoform 3 play a key role in the regulation of the levels of PSEN1 by targeting its accumulation to aggresomes which may then be removed from cells by autophagocytosis (PubMed:21143716). Promotes the ubiquitination and lysosomal degradation of ORAI1, consequently downregulating the ORAI1-mediated Ca2+ mobilization (PubMed:23307288). Suppresses the maturation and proteasomal degradation of amyloid beta A4 protein (A4) by stimulating the lysine 63 (K63)-linked polyubiquitination. Delays the maturation of A4 by sequestering it in the Golgi apparatus and preventing its transport to the cell surface for subsequent processing (By similarity). {ECO:0000250|UniProtKB:Q9JJP9, ECO:0000269|PubMed:18307982, ECO:0000269|PubMed:18953672, ECO:0000269|PubMed:19148225, ECO:0000269|PubMed:19822669, ECO:0000269|PubMed:20529957, ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:21695056, ECO:0000269|PubMed:23307288, ECO:0000269|PubMed:23459205, ECO:0000303|PubMed:15147878}.

Subunit: Monomer and homodimer. Heterodimer with UBQLN2 (PubMed:16813565). Binds CD47, NBL1, GABRA1, GABRA2, GABRA3, GABRA6, GABRB1, GABRB2 and GABRB3 (By similarity). Binds UBE3A, BTRC, P4HB and MTOR. Interacts with the proteasome 19S subunit. Interacts (via ubiquitin-like domain) with TREX1; the interaction is direct and may control TREX1 subcellular location. Forms a complex with UBXN4 and VCP. Interacts (via UBA domain) with UBQLN4 (via ubiquitin-like domain). Found in a complex with UBQLN2 and MAP1LC3A/B/C. The monomeric form interacts with PSEN2 and the monomeric forms of isoform 1 and isoform 3 interact with PSEN1. Interacts with ORAI1. Interacts (via UBA domain) with TICAM1. Interacts with EPS15. Interacts (via UBA domain) with UBA52 and (via ubiquitin-like domain) with PSMD3 and PSMD4. Interacts with HERPUD1. Interacts with MAP1LC3A/B/C in the presence of UBQLN4. Interacts (via ubiquitin-like domain) with EPS15 (via UIM domains) and both the ubiquitinated and non-ubiquitinated forms can interact with EPS15. Interacts (via ubiquitin-like domain) with EPS15L1, HGS (via UIM domain) and STAM2 (via UIM domain). {ECO:0000250|UniProtKB:Q8R317, ECO:0000250|UniProtKB:Q9JJP9, ECO:0000269|PubMed:10983987, ECO:0000269|PubMed:11076969, ECO:0000269|PubMed:11853878, ECO:0000269|PubMed:12095988, ECO:0000269|PubMed:15147878, ECO:0000269|PubMed:16159959, ECO:0000269|PubMed:16813565, ECO:0000269|PubMed:18199683, ECO:0000269|PubMed:18241885, ECO:0000269|PubMed:18307982, ECO:0000269|PubMed:19822669, ECO:0000269|PubMed:20529957, ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:21695056, ECO:0000269|PubMed:23307288, ECO:0000269|PubMed:23459205, ECO:0000269|PubMed:23979357}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:16159959, ECO:0000269|PubMed:23979357}. Nucleus {ECO:0000269|PubMed:23979357}. Endoplasmic reticulum {ECO:0000269|PubMed:19822669}. Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:19148225, ECO:0000269|PubMed:20529957, ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:21695056, ECO:0000269|PubMed:23307288, ECO:0000269|PubMed:23459205}. Cell membrane {ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:23307288}. Note=Detected in neuronal processes and at synapses (By similarity). Recruited to the ER during ER-associated protein degradation (ERAD) (PubMed:19822669). Isoform 1 and isoform 3 colocalize with PSEN1 in the cell membrane and in cytoplasmic juxtanuclear structures called aggresomes (PubMed:21143716). Colocalizes with ORAI1 and TICAM1 in the autophagosome (PubMed:23307288, PubMed:21695056). Colocalizes with EPS15 and HGS in ubiquitin-rich cytoplasmic aggregates that are not endocytic compartments and with EPS15 also in aggresomes (PubMed:16159959). {ECO:0000250|UniProtKB:Q9JJP9, ECO:0000269|PubMed:16159959, ECO:0000269|PubMed:19822669, ECO:0000269|PubMed:21143716, ECO:0000269|PubMed:21695056, ECO:0000269|PubMed:23307288}.

Tissue specificity: Brain (at protein level) (PubMed:18953672). Ubiquitous. Highly expressed throughout the brain; detected in neurons and in neuropathological lesions, such as neurofibrillary tangles and Lewy bodies. Highly expressed in heart, placenta, pancreas, lung, liver, skeletal muscle and kidney. {ECO:0000269|PubMed:11076969, ECO:0000269|PubMed:11853878, ECO:0000269|PubMed:18953672}.

Domain: The UBA domain mediates binding to PSEN1 and PSEN2. It also binds ubiquitin with micromolar affinity, independently of polyubiquitin linkage type. Essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3). {ECO:0000269|PubMed:11076969, ECO:0000269|PubMed:15147878, ECO:0000269|PubMed:19148225}.

Domain: The ubiquitin-like domain mediates its association with the subunits of the proteasome. {ECO:0000269|PubMed:15147878}.

Domain: Dimerization is dependent upon the central region of the protein containing the STI1 domains and is independent of its ubiquitin-like and UBA domains. {ECO:0000269|PubMed:16813565}.

Ptm: Degraded during both macroautophagy and during chaperone-mediated autophagy (CMA). {ECO:0000269|PubMed:20529957}.

Ptm: Phosphorylated. {ECO:0000269|PubMed:11853878}.

Ptm: Ubiquitinated. {ECO:0000269|PubMed:16159959}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin- proteasome system (UPS), autophagy and endoplasmic reticulum-associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome (PubMed:15147878). Plays a role in the ERAD pathway via its interaction with ER-localized proteins UBXN4, VCP and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:19822669, PubMed:18307982). Isoform 1, isoform 2 and isoform 3 play a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress (PubMed:18953672). Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy- related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:19148225, PubMed:20529957, PubMed:23459205). Negatively regulates the TICAM1/TRIF-dependent toll-like receptor signaling pathway by decreasing the abundance of TICAM1 via the autophagic pathway (PubMed:21695056). Isoform 1 and isoform 3 play a key role in the regulation of the levels of PSEN1 by targeting its accumulation to aggresomes which may then be removed from cells by autophagocytosis (PubMed:21143716). Promotes the ubiquitination and lysosomal degradation of ORAI1, consequently downregulating the ORAI1-mediated Ca2+ mobilization (PubMed:23307288). Suppresses the maturation and proteasomal degradation of amyloid beta A4 protein (A4) by stimulating the lysine 63 (K63)-linked polyubiquitination. Delays the maturation of A4 by sequestering it in the Golgi apparatus and preventing its transport to the cell surface for subsequent processing (By similarity). {ECO:0000250\|UniProtKB:Q9JJP9, ECO:0000269\|PubMed:18307982, ECO:0000269\|PubMed:18953672, ECO:0000269\|PubMed:19148225, ECO:0000269\|PubMed:19822669, ECO:0000269\|PubMed:20529957, ECO:0000269\|PubMed:21143716, ECO:0000269\|PubMed:21695056, ECO:0000269\|PubMed:23307288, ECO:0000269\|PubMed:23459205, ECO:0000303\|PubMed:15147878}.


Subunit:		Monomer and homodimer. Heterodimer with UBQLN2 (PubMed:16813565). Binds CD47, NBL1, GABRA1, GABRA2, GABRA3, GABRA6, GABRB1, GABRB2 and GABRB3 (By similarity). Binds UBE3A, BTRC, P4HB and MTOR. Interacts with the proteasome 19S subunit. Interacts (via ubiquitin-like domain) with TREX1; the interaction is direct and may control TREX1 subcellular location. Forms a complex with UBXN4 and VCP. Interacts (via UBA domain) with UBQLN4 (via ubiquitin-like domain). Found in a complex with UBQLN2 and MAP1LC3A/B/C. The monomeric form interacts with PSEN2 and the monomeric forms of isoform 1 and isoform 3 interact with PSEN1. Interacts with ORAI1. Interacts (via UBA domain) with TICAM1. Interacts with EPS15. Interacts (via UBA domain) with UBA52 and (via ubiquitin-like domain) with PSMD3 and PSMD4. Interacts with HERPUD1. Interacts with MAP1LC3A/B/C in the presence of UBQLN4. Interacts (via ubiquitin-like domain) with EPS15 (via UIM domains) and both the ubiquitinated and non-ubiquitinated forms can interact with EPS15. Interacts (via ubiquitin-like domain) with EPS15L1, HGS (via UIM domain) and STAM2 (via UIM domain). {ECO:0000250\|UniProtKB:Q8R317, ECO:0000250\|UniProtKB:Q9JJP9, ECO:0000269\|PubMed:10983987, ECO:0000269\|PubMed:11076969, ECO:0000269\|PubMed:11853878, ECO:0000269\|PubMed:12095988, ECO:0000269\|PubMed:15147878, ECO:0000269\|PubMed:16159959, ECO:0000269\|PubMed:16813565, ECO:0000269\|PubMed:18199683, ECO:0000269\|PubMed:18241885, ECO:0000269\|PubMed:18307982, ECO:0000269\|PubMed:19822669, ECO:0000269\|PubMed:20529957, ECO:0000269\|PubMed:21143716, ECO:0000269\|PubMed:21695056, ECO:0000269\|PubMed:23307288, ECO:0000269\|PubMed:23459205, ECO:0000269\|PubMed:23979357}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:16159959, ECO:0000269\|PubMed:23979357}. Nucleus {ECO:0000269\|PubMed:23979357}. Endoplasmic reticulum {ECO:0000269\|PubMed:19822669}. Cytoplasmic vesicle, autophagosome {ECO:0000269\|PubMed:19148225, ECO:0000269\|PubMed:20529957, ECO:0000269\|PubMed:21143716, ECO:0000269\|PubMed:21695056, ECO:0000269\|PubMed:23307288, ECO:0000269\|PubMed:23459205}. Cell membrane {ECO:0000269\|PubMed:21143716, ECO:0000269\|PubMed:23307288}. Note=Detected in neuronal processes and at synapses (By similarity). Recruited to the ER during ER-associated protein degradation (ERAD) (PubMed:19822669). Isoform 1 and isoform 3 colocalize with PSEN1 in the cell membrane and in cytoplasmic juxtanuclear structures called aggresomes (PubMed:21143716). Colocalizes with ORAI1 and TICAM1 in the autophagosome (PubMed:23307288, PubMed:21695056). Colocalizes with EPS15 and HGS in ubiquitin-rich cytoplasmic aggregates that are not endocytic compartments and with EPS15 also in aggresomes (PubMed:16159959). {ECO:0000250\|UniProtKB:Q9JJP9, ECO:0000269\|PubMed:16159959, ECO:0000269\|PubMed:19822669, ECO:0000269\|PubMed:21143716, ECO:0000269\|PubMed:21695056, ECO:0000269\|PubMed:23307288}.
Tissue specificity:		Brain (at protein level) (PubMed:18953672). Ubiquitous. Highly expressed throughout the brain; detected in neurons and in neuropathological lesions, such as neurofibrillary tangles and Lewy bodies. Highly expressed in heart, placenta, pancreas, lung, liver, skeletal muscle and kidney. {ECO:0000269\|PubMed:11076969, ECO:0000269\|PubMed:11853878, ECO:0000269\|PubMed:18953672}.
Domain:		The UBA domain mediates binding to PSEN1 and PSEN2. It also binds ubiquitin with micromolar affinity, independently of polyubiquitin linkage type. Essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3). {ECO:0000269\|PubMed:11076969, ECO:0000269\|PubMed:15147878, ECO:0000269\|PubMed:19148225}.
Domain:		The ubiquitin-like domain mediates its association with the subunits of the proteasome. {ECO:0000269\|PubMed:15147878}.
Domain:		Dimerization is dependent upon the central region of the protein containing the STI1 domains and is independent of its ubiquitin-like and UBA domains. {ECO:0000269\|PubMed:16813565}.
Ptm:		Degraded during both macroautophagy and during chaperone-mediated autophagy (CMA). {ECO:0000269\|PubMed:20529957}.
Ptm:		Phosphorylated. {ECO:0000269\|PubMed:11853878}.
Ptm:		Ubiquitinated. {ECO:0000269\|PubMed:16159959}.