UniProt functional annotation for Q9UHD9



	UniProt functional annotation for Q9UHD9

UniProt code: Q9UHD9.

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 the 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:10983987). Plays a role in the ERAD pathway via its interaction with ER-localized proteins FAF2/UBXD8 and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:24215460, PubMed:18307982). 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). Negatively regulates the endocytosis of GPCR receptors: AVPR2 and ADRB2, by specifically reducing the rate at which receptor-arrestin complexes concentrate in clathrin-coated pits (CCPs) (PubMed:18199683). {ECO:0000269|PubMed:10983987, ECO:0000269|PubMed:18199683, ECO:0000269|PubMed:18307982, ECO:0000269|PubMed:19148225, ECO:0000269|PubMed:20529957, ECO:0000269|PubMed:24215460}.

Subunit: Homodimer. Forms heterodimer with UBQLN1. Binds UBE3A and BTRC. Interacts with the 19S proteasome subunit. Interacts with C9orf72. Interacts with HNRNPA1 and HNRNPU. Found in a complex with UBQLN1 and MAP1LC3A/B/C. Interacts with EPS15, EPN1 and EPN2. Interacts with HERPUD1. Interacts with RAD23A. Interacts with TARDBP. Interacts (via C-terminus) with FAF2 (via N-terminus). Interacts with UBQLN4. Binds CD47 (By similarity). {ECO:0000250|UniProtKB:Q9QZM0, ECO:0000269|PubMed:10675567, ECO:0000269|PubMed:10983987, ECO:0000269|PubMed:16813565, ECO:0000269|PubMed:17098253, ECO:0000269|PubMed:18199683, ECO:0000269|PubMed:18307982, ECO:0000269|PubMed:20529957, ECO:0000269|PubMed:23459205, ECO:0000269|PubMed:23541532, ECO:0000269|PubMed:24215460, ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:25616961}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:18199683}. Nucleus {ECO:0000269|PubMed:9853615}. Membrane {ECO:0000250|UniProtKB:Q9QZM0}. Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:19148225}. Note=Colocalizes with a subset of proteasomes, namely those that are cytoskeleton associated or free in the cytosol. Associated with fibers in mitotic cells. {ECO:0000269|PubMed:10983987}.

Induction: Highly expressed in mitotic cells from metaphase to telophase. Expression in non-mitotic cells is very low.

Domain: The ubiquitin-like domain is essential for its inhibitory effect on GPCR endocytosis. Mediates its association with the subunits of the proteasome. {ECO:0000269|PubMed:18199683, ECO:0000303|PubMed:24589709}.

Domain: The UBA domain is essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3). Mediates its association with ubiquitinated substrates. {ECO:0000269|PubMed:19148225, ECO:0000303|PubMed:24589709}.

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 macroautophagy. {ECO:0000269|PubMed:20529957}.

Disease: Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (ALS15) [MIM:300857]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS15 may develop frontotemporal dementia. {ECO:0000269|PubMed:21857683, ECO:0000269|PubMed:22560112, ECO:0000269|PubMed:22717235, ECO:0000269|PubMed:22892309, ECO:0000269|PubMed:24215460, ECO:0000269|PubMed:25616961}. Note=The disease is caused by variants affecting the gene represented in this entry.

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 the 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:10983987). Plays a role in the ERAD pathway via its interaction with ER-localized proteins FAF2/UBXD8 and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome (PubMed:24215460, PubMed:18307982). 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). Negatively regulates the endocytosis of GPCR receptors: AVPR2 and ADRB2, by specifically reducing the rate at which receptor-arrestin complexes concentrate in clathrin-coated pits (CCPs) (PubMed:18199683). {ECO:0000269\|PubMed:10983987, ECO:0000269\|PubMed:18199683, ECO:0000269\|PubMed:18307982, ECO:0000269\|PubMed:19148225, ECO:0000269\|PubMed:20529957, ECO:0000269\|PubMed:24215460}.


Subunit:		Homodimer. Forms heterodimer with UBQLN1. Binds UBE3A and BTRC. Interacts with the 19S proteasome subunit. Interacts with C9orf72. Interacts with HNRNPA1 and HNRNPU. Found in a complex with UBQLN1 and MAP1LC3A/B/C. Interacts with EPS15, EPN1 and EPN2. Interacts with HERPUD1. Interacts with RAD23A. Interacts with TARDBP. Interacts (via C-terminus) with FAF2 (via N-terminus). Interacts with UBQLN4. Binds CD47 (By similarity). {ECO:0000250\|UniProtKB:Q9QZM0, ECO:0000269\|PubMed:10675567, ECO:0000269\|PubMed:10983987, ECO:0000269\|PubMed:16813565, ECO:0000269\|PubMed:17098253, ECO:0000269\|PubMed:18199683, ECO:0000269\|PubMed:18307982, ECO:0000269\|PubMed:20529957, ECO:0000269\|PubMed:23459205, ECO:0000269\|PubMed:23541532, ECO:0000269\|PubMed:24215460, ECO:0000269\|PubMed:24549040, ECO:0000269\|PubMed:25616961}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:18199683}. Nucleus {ECO:0000269\|PubMed:9853615}. Membrane {ECO:0000250\|UniProtKB:Q9QZM0}. Cytoplasmic vesicle, autophagosome {ECO:0000269\|PubMed:19148225}. Note=Colocalizes with a subset of proteasomes, namely those that are cytoskeleton associated or free in the cytosol. Associated with fibers in mitotic cells. {ECO:0000269\|PubMed:10983987}.
Induction:		Highly expressed in mitotic cells from metaphase to telophase. Expression in non-mitotic cells is very low.
Domain:		The ubiquitin-like domain is essential for its inhibitory effect on GPCR endocytosis. Mediates its association with the subunits of the proteasome. {ECO:0000269\|PubMed:18199683, ECO:0000303\|PubMed:24589709}.
Domain:		The UBA domain is essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3). Mediates its association with ubiquitinated substrates. {ECO:0000269\|PubMed:19148225, ECO:0000303\|PubMed:24589709}.
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 macroautophagy. {ECO:0000269\|PubMed:20529957}.
Disease:		Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (ALS15) [MIM:300857]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS15 may develop frontotemporal dementia. {ECO:0000269\|PubMed:21857683, ECO:0000269\|PubMed:22560112, ECO:0000269\|PubMed:22717235, ECO:0000269\|PubMed:22892309, ECO:0000269\|PubMed:24215460, ECO:0000269\|PubMed:25616961}. Note=The disease is caused by variants affecting the gene represented in this entry.