UniProt functional annotation for Q9UNE7



	UniProt functional annotation for Q9UNE7

UniProt code: Q9UNE7.

Organism: Homo sapiens (Human).

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

Function: E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base- excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB- degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation (PubMed:27708256). Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B- dependent manner (PubMed:23973223). Likely mediates polyubiquitination and downregulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation (PubMed:24613385). May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation (PubMed:17369820). Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation (PubMed:29883609). {ECO:0000269|PubMed:10330192, ECO:0000269|PubMed:11146632, ECO:0000269|PubMed:11557750, ECO:0000269|PubMed:15466472, ECO:0000269|PubMed:17369820, ECO:0000269|PubMed:19103148, ECO:0000269|PubMed:19567782, ECO:0000269|PubMed:19713937, ECO:0000269|PubMed:23973223, ECO:0000269|PubMed:23990462, ECO:0000269|PubMed:24613385, ECO:0000269|PubMed:28813410, ECO:0000269|PubMed:29883609}.

Catalytic activity: Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.27; Evidence={ECO:0000269|PubMed:11557750, ECO:0000269|PubMed:15466472};

Pathway: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:11557750, ECO:0000269|PubMed:15466472}.

Subunit: Homodimer (By similarity). Interacts with BAG2 (PubMed:16169850). Interacts with E2 ubiquitin conjugating enzymes UBE2D1, UBE2D2 and UBE2D3 (PubMed:11557750). Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1 (PubMed:15215316). Interacts with MKKS (PubMed:18094050). Interacts with DNAAF4 (PubMed:19423554). Interacts with POLB (PubMed:19713937). Interacts (when monoubiquitinated) with ATXN3. Interacts with UBE2W. Interacts (via the U-box domain) with the UBE2V2-UBE2N heterodimer; the complex has a specific 'Lys-63'-linked polyubiquitination activity (By similarity). Interacts with DNAJB6 (PubMed:22366786). Interacts with FOXP3 (PubMed:23973223). Interacts with FLCN (PubMed:27353360). Interacts with HSP90AA1 (PubMed:27353360, PubMed:24613385). Interacts with HSP90 (PubMed:11146632). Interacts with UBE2N and UBE2V1 (PubMed:16307917). Interacts (via TPR repeats) with the C-terminal domain of HSPA1A (PubMed:10330192). Interacts with the non-acetylated form of HSPA1A and HSPA1B (PubMed:27708256). Interacts (via TPR repeats) with the C-terminal domain of HSPA8 (PubMed:10330192, PubMed:11557750, PubMed:23990462, PubMed:27708256). Interacts with SMAD3 and HSP90AB1 (PubMed:24613385). Interacts with UBE4B (PubMed:17369820). Interacts with RIPK3 (PubMed:29883609). Interacts with PRMT5 (PubMed:33376131). {ECO:0000250|UniProtKB:Q9WUD1, ECO:0000269|PubMed:10330192, ECO:0000269|PubMed:11146632, ECO:0000269|PubMed:11557750, ECO:0000269|PubMed:15215316, ECO:0000269|PubMed:16169850, ECO:0000269|PubMed:16307917, ECO:0000269|PubMed:17369820, ECO:0000269|PubMed:18094050, ECO:0000269|PubMed:19423554, ECO:0000269|PubMed:19713937, ECO:0000269|PubMed:22366786, ECO:0000269|PubMed:23973223, ECO:0000269|PubMed:23990462, ECO:0000269|PubMed:24613385, ECO:0000269|PubMed:27353360, ECO:0000269|PubMed:27708256, ECO:0000269|PubMed:29883609}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:10330192, ECO:0000269|PubMed:17369820, ECO:0000269|PubMed:23973223}. Nucleus {ECO:0000269|PubMed:23973223}. Note=Translocates to the nucleus in response to inflammatory signals in regulatory T-cells (Treg). {ECO:0000269|PubMed:23973223}.

Tissue specificity: Expressed in differentiated myotubes (at protein level) (PubMed:17369820). Highly expressed in skeletal muscle, heart, pancreas, brain and placenta (PubMed:10330192, PubMed:11435423). Detected in kidney, liver and lung (PubMed:10330192, PubMed:11435423). {ECO:0000269|PubMed:10330192, ECO:0000269|PubMed:11435423, ECO:0000269|PubMed:17369820}.

Induction: Up-regulated by inflammatory signals in regulatory T-cells (Treg). {ECO:0000269|PubMed:23973223}.

Domain: The U-box domain is required for the ubiquitin protein ligase activity. {ECO:0000250|UniProtKB:Q9WUD1}.

Domain: The TPR domain is essential for ubiquitination mediated by UBE2D1. {ECO:0000269|PubMed:18042044}.

Ptm: Monoubiquitinated at Lys-2 following cell stress by UBE2W, promoting the interaction with ATXN3 (By similarity). Auto- ubiquitinated; mediated by UBE2D1 and UBE2D2. {ECO:0000250, ECO:0000269|PubMed:18042044, ECO:0000269|PubMed:23560854}.

Disease: Spinocerebellar ataxia, autosomal recessive, 16 (SCAR16) [MIM:615768]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR16 is characterized by truncal and limb ataxia resulting in gait instability. Additionally, patients may show dysarthria, nystagmus, spasticity of the lower limbs, and mild peripheral sensory neuropathy. {ECO:0000269|PubMed:24113144, ECO:0000269|PubMed:24312598, ECO:0000269|PubMed:24719489, ECO:0000269|PubMed:24742043, ECO:0000269|PubMed:25258038}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Spinocerebellar ataxia 48 (SCA48) [MIM:618093]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA48 is an autosomal dominant neurodegenerative disease characterized by onset in mid-adulthood of progressive cognitive decline and gait ataxia, and vermian and hemispheric cerebellar atrophy. {ECO:0000269|PubMed:30381368}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: Antibodies against STUB1 are found in patients with chronic lymphocytic leukemia (CLL) and in colorectal cancer patients.

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:		E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base- excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB- degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation (PubMed:27708256). Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B- dependent manner (PubMed:23973223). Likely mediates polyubiquitination and downregulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation (PubMed:24613385). May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation (PubMed:17369820). Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation (PubMed:29883609). {ECO:0000269\|PubMed:10330192, ECO:0000269\|PubMed:11146632, ECO:0000269\|PubMed:11557750, ECO:0000269\|PubMed:15466472, ECO:0000269\|PubMed:17369820, ECO:0000269\|PubMed:19103148, ECO:0000269\|PubMed:19567782, ECO:0000269\|PubMed:19713937, ECO:0000269\|PubMed:23973223, ECO:0000269\|PubMed:23990462, ECO:0000269\|PubMed:24613385, ECO:0000269\|PubMed:28813410, ECO:0000269\|PubMed:29883609}.


Catalytic activity:		Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.27; Evidence={ECO:0000269\|PubMed:11557750, ECO:0000269\|PubMed:15466472};
Pathway:		Protein modification; protein ubiquitination. {ECO:0000269\|PubMed:11557750, ECO:0000269\|PubMed:15466472}.
Subunit:		Homodimer (By similarity). Interacts with BAG2 (PubMed:16169850). Interacts with E2 ubiquitin conjugating enzymes UBE2D1, UBE2D2 and UBE2D3 (PubMed:11557750). Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1 (PubMed:15215316). Interacts with MKKS (PubMed:18094050). Interacts with DNAAF4 (PubMed:19423554). Interacts with POLB (PubMed:19713937). Interacts (when monoubiquitinated) with ATXN3. Interacts with UBE2W. Interacts (via the U-box domain) with the UBE2V2-UBE2N heterodimer; the complex has a specific 'Lys-63'-linked polyubiquitination activity (By similarity). Interacts with DNAJB6 (PubMed:22366786). Interacts with FOXP3 (PubMed:23973223). Interacts with FLCN (PubMed:27353360). Interacts with HSP90AA1 (PubMed:27353360, PubMed:24613385). Interacts with HSP90 (PubMed:11146632). Interacts with UBE2N and UBE2V1 (PubMed:16307917). Interacts (via TPR repeats) with the C-terminal domain of HSPA1A (PubMed:10330192). Interacts with the non-acetylated form of HSPA1A and HSPA1B (PubMed:27708256). Interacts (via TPR repeats) with the C-terminal domain of HSPA8 (PubMed:10330192, PubMed:11557750, PubMed:23990462, PubMed:27708256). Interacts with SMAD3 and HSP90AB1 (PubMed:24613385). Interacts with UBE4B (PubMed:17369820). Interacts with RIPK3 (PubMed:29883609). Interacts with PRMT5 (PubMed:33376131). {ECO:0000250\|UniProtKB:Q9WUD1, ECO:0000269\|PubMed:10330192, ECO:0000269\|PubMed:11146632, ECO:0000269\|PubMed:11557750, ECO:0000269\|PubMed:15215316, ECO:0000269\|PubMed:16169850, ECO:0000269\|PubMed:16307917, ECO:0000269\|PubMed:17369820, ECO:0000269\|PubMed:18094050, ECO:0000269\|PubMed:19423554, ECO:0000269\|PubMed:19713937, ECO:0000269\|PubMed:22366786, ECO:0000269\|PubMed:23973223, ECO:0000269\|PubMed:23990462, ECO:0000269\|PubMed:24613385, ECO:0000269\|PubMed:27353360, ECO:0000269\|PubMed:27708256, ECO:0000269\|PubMed:29883609}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:10330192, ECO:0000269\|PubMed:17369820, ECO:0000269\|PubMed:23973223}. Nucleus {ECO:0000269\|PubMed:23973223}. Note=Translocates to the nucleus in response to inflammatory signals in regulatory T-cells (Treg). {ECO:0000269\|PubMed:23973223}.
Tissue specificity:		Expressed in differentiated myotubes (at protein level) (PubMed:17369820). Highly expressed in skeletal muscle, heart, pancreas, brain and placenta (PubMed:10330192, PubMed:11435423). Detected in kidney, liver and lung (PubMed:10330192, PubMed:11435423). {ECO:0000269\|PubMed:10330192, ECO:0000269\|PubMed:11435423, ECO:0000269\|PubMed:17369820}.
Induction:		Up-regulated by inflammatory signals in regulatory T-cells (Treg). {ECO:0000269\|PubMed:23973223}.
Domain:		The U-box domain is required for the ubiquitin protein ligase activity. {ECO:0000250\|UniProtKB:Q9WUD1}.
Domain:		The TPR domain is essential for ubiquitination mediated by UBE2D1. {ECO:0000269\|PubMed:18042044}.
Ptm:		Monoubiquitinated at Lys-2 following cell stress by UBE2W, promoting the interaction with ATXN3 (By similarity). Auto- ubiquitinated; mediated by UBE2D1 and UBE2D2. {ECO:0000250, ECO:0000269\|PubMed:18042044, ECO:0000269\|PubMed:23560854}.
Disease:		Spinocerebellar ataxia, autosomal recessive, 16 (SCAR16) [MIM:615768]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR16 is characterized by truncal and limb ataxia resulting in gait instability. Additionally, patients may show dysarthria, nystagmus, spasticity of the lower limbs, and mild peripheral sensory neuropathy. {ECO:0000269\|PubMed:24113144, ECO:0000269\|PubMed:24312598, ECO:0000269\|PubMed:24719489, ECO:0000269\|PubMed:24742043, ECO:0000269\|PubMed:25258038}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Spinocerebellar ataxia 48 (SCA48) [MIM:618093]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA48 is an autosomal dominant neurodegenerative disease characterized by onset in mid-adulthood of progressive cognitive decline and gait ataxia, and vermian and hemispheric cerebellar atrophy. {ECO:0000269\|PubMed:30381368}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		Antibodies against STUB1 are found in patients with chronic lymphocytic leukemia (CLL) and in colorectal cancer patients.