UniProt functional annotation for Q4VGL6



	UniProt functional annotation for Q4VGL6

UniProt code: Q4VGL6.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3'-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more mRNAs (PubMed:23663784, PubMed:25026077, PubMed:18172933). Cleaves translationally inactive mRNAs harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-independent manner (PubMed:26000482). Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs (PubMed:20412057, PubMed:20639877). In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4/Ox40 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity. In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression. Also recognizes CDE in its own mRNA and in that of paralogous RC3H2, possibly leading to feedback loop regulation (PubMed:23583642, PubMed:23583643, PubMed:15917799). Inhibits cooperatively with ZC3H12A the differentiation of helper T cells Th17 in lungs. They repress target mRNA encoding the Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ. The cooperation requires RNA-binding by RC3H1 and the nuclease activity of ZC3H12A (PubMed:25282160). Recognizes and binds mRNAs containing a hexaloop stem-loop motif, called alternative decay element (ADE) (PubMed:27010430). Together with ZC3H12A, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (PubMed:29244194). Able to interact with double- stranded RNA (By similarity). miRNA-binding protein that regulates microRNA homeostasis. Enhances DICER-mediated processing of pre-MIR146a but reduces mature MIR146a levels through an increase of 3' end uridylation. Both inhibits ICOS mRNA expression and they may act together to exert the suppression (PubMed:25697406). Acts as a ubiquitin E3 ligase. Pairs with E2 enzymes UBE2A, UBE2B, UBE2D2, UBE2F, UBE2G1, UBE2G2 and UBE2L3 and produces polyubiquitin chains. Shows the strongest activity when paired with UBE2N:UBE2V1 or UBE2N:UBE2V2 E2 complexes and generate both short and long polyubiquitin chains (By similarity). {ECO:0000250|UniProtKB:Q5TC82, ECO:0000269|PubMed:15917799, ECO:0000269|PubMed:18172933, ECO:0000269|PubMed:20412057, ECO:0000269|PubMed:20639877, ECO:0000269|PubMed:23583642, ECO:0000269|PubMed:23583643, ECO:0000269|PubMed:23663784, ECO:0000269|PubMed:25026077, ECO:0000269|PubMed:25282160, ECO:0000269|PubMed:25697406, ECO:0000269|PubMed:26000482, ECO:0000269|PubMed:27010430, ECO:0000269|PubMed:29244194}.

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:0000250|UniProtKB:Q5TC82};

Pathway: Protein modification; protein ubiquitination. {ECO:0000250|UniProtKB:Q5TC82}.

Subunit: Interacts with DDX6 and EDC4 (PubMed:20639877, PubMed:23583643). Interacts with CCR4-NOT deadenylase complex (PubMed:23663784). Interacts with RC3H1; the interaction is RNA independent (PubMed:25697406). {ECO:0000269|PubMed:20639877, ECO:0000269|PubMed:23583643, ECO:0000269|PubMed:23663784, ECO:0000269|PubMed:25697406}.

Subcellular location: Cytoplasm, P-body {ECO:0000269|PubMed:15917799, ECO:0000269|PubMed:20412057, ECO:0000269|PubMed:20639877, ECO:0000269|PubMed:23583642, ECO:0000269|PubMed:26000482}. Cytoplasmic granule {ECO:0000269|PubMed:26000482}. Note=During stress, such as that induced by arsenite treatment, localizes to cytosolic stress granules (PubMed:26000482). Localization to stress granules, but not to P- bodies, depends upon the RING-type zinc finger. ICOS repression may correlate with the localization to P-bodies, not to stress granules (PubMed:20639877). {ECO:0000269|PubMed:20639877, ECO:0000269|PubMed:26000482}.

Tissue specificity: Widely expressed, with highest levels in lymph node and thymus and slightly lesser amounts in brain, lung, and spleen (at protein level) (PubMed:23583643). Very weak expression in heart, muscle, and kidney (at protein level) (PubMed:23583643). Expressed in CD4(+) helper T-cells (at protein level) (PubMed:29244194, PubMed:15917799, PubMed:23583643). {ECO:0000269|PubMed:15917799, ECO:0000269|PubMed:23583643, ECO:0000269|PubMed:29244194}.

Domain: The ROQ region is required for CDE RNA-binding (PubMed:27010430, PubMed:25026077, PubMed:23663784). Has 2 separate RNA-binding sites, one for CDE RNA and the other for dsRNA, both sites are important for mRNA decay (By similarity). ADE RNA-binding involves an extended binding surface on the ROQ region with a number of additional residues compared with the CDE RNA (PubMed:27010430). It may also be involved in localization to stress granules (PubMed:20412057, PubMed:23583642). {ECO:0000250|UniProtKB:Q5TC82, ECO:0000269|PubMed:20412057, ECO:0000269|PubMed:23583642, ECO:0000269|PubMed:23663784, ECO:0000269|PubMed:25026077, ECO:0000269|PubMed:27010430}.

Domain: The RING-type zinc finger may be required for proper localization to stress granules, but not to P-bodies. {ECO:0000269|PubMed:23583642}.

Domain: HEPN (higher eukaryotes and prokaryotes nucleotide-binding) are observed in both N- and C-terminal sides of ROQ domain with 3D structure even if they are poredcted on the basis of sequence. {ECO:0000269|PubMed:25697406}.

Ptm: Proteolytically cleaved after Arg-510 and Arg-579 by MALT1 in activated CD4(+) T cells; cleavage at Arg-510 and Arg-579 is critical for promoting RC3H1 degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling Th17 cell differentiation. {ECO:0000269|PubMed:25282160}.

Disruption phenotype: Mutant animals are born at Mendelian ratio, but die within 6 hours after birth. They displayed a curly tail and malformations of the caudal spinal column. Lethality can be rescued by changing the genetic background from C57BL/6 to outbred CD1, which allows about 4% of the animals to survive to adulthood. These animals display enlarged spleens with a trend toward increased numbers of eosinophils and monocytic/macrophage populations, dramatic and selective expansion of CD8(+) effector-like T-cells. Splenic follicular organization is normal, and the numbers of CD4(+) T-cell subtypes and B-cells are not significantly altered. No spontaneous germinal center formation, autoantibody production, nor autoimmune tissue damage. Ablation of Rc3h1 gene in the T lineage leads to elevated ICOS levels and expansion of effector CD8(+) T-cells, but not autoimmunity (PubMed:21844204). Mice lacking both Rc3h1 and Rc3h2 genes in CD4(+) T- cells develop lymphadenopathy and splenomegaly with increased spleen weight and cellularity, already at young age. They show a prominent lung pathology with a progressive reduction in the alveolar space concomitant with inflammation. They show an average survival of 130 days. CD4(+) T-cells of these mutants show a pronounced bias toward Th17 differentiation (PubMed:21844204, PubMed:23583643). {ECO:0000269|PubMed:21844204, ECO:0000269|PubMed:23583643}.

Miscellaneous: Treatment of C57BL/6 males with ethylnitrosourea led to the identification of the sanroque mouse strain. The causative mutation in sanroque appears to be RC3H1 Arg-199. Homozygous sanroque mice develop high titers of autoantibodies and display excessive numbers of follicular helper T-cells and germinal centers with pattern of pathology consistent with lupus (PubMed:15917799). Sanroque mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Extensive cytokine dysregulation resulting in both over- expression and under-expression of chemotactic cytokines occurs in the ileum, the region most prone to the development of inflammation in sanroque mice (PubMed:23451046). They show up-regulation of expression of at least 15 miRNAs in T cells (PubMed:25697406). The lack of compensation of RC3H1 defects by the RC3H2 paralog in sanroque mice may be due to the fact that the mutated protein may retain its scaffolding position within RNA granules, preventing RC3H2 to access mRNAs to be regulated (PubMed:23583642). {ECO:0000269|PubMed:25697406, ECO:0000305|PubMed:15917799, ECO:0000305|PubMed:23451046, ECO:0000305|PubMed:23583642}.

Sequence caution: Sequence=BAD32613.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3'-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more mRNAs (PubMed:23663784, PubMed:25026077, PubMed:18172933). Cleaves translationally inactive mRNAs harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-independent manner (PubMed:26000482). Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs (PubMed:20412057, PubMed:20639877). In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4/Ox40 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity. In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression. Also recognizes CDE in its own mRNA and in that of paralogous RC3H2, possibly leading to feedback loop regulation (PubMed:23583642, PubMed:23583643, PubMed:15917799). Inhibits cooperatively with ZC3H12A the differentiation of helper T cells Th17 in lungs. They repress target mRNA encoding the Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ. The cooperation requires RNA-binding by RC3H1 and the nuclease activity of ZC3H12A (PubMed:25282160). Recognizes and binds mRNAs containing a hexaloop stem-loop motif, called alternative decay element (ADE) (PubMed:27010430). Together with ZC3H12A, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (PubMed:29244194). Able to interact with double- stranded RNA (By similarity). miRNA-binding protein that regulates microRNA homeostasis. Enhances DICER-mediated processing of pre-MIR146a but reduces mature MIR146a levels through an increase of 3' end uridylation. Both inhibits ICOS mRNA expression and they may act together to exert the suppression (PubMed:25697406). Acts as a ubiquitin E3 ligase. Pairs with E2 enzymes UBE2A, UBE2B, UBE2D2, UBE2F, UBE2G1, UBE2G2 and UBE2L3 and produces polyubiquitin chains. Shows the strongest activity when paired with UBE2N:UBE2V1 or UBE2N:UBE2V2 E2 complexes and generate both short and long polyubiquitin chains (By similarity). {ECO:0000250\|UniProtKB:Q5TC82, ECO:0000269\|PubMed:15917799, ECO:0000269\|PubMed:18172933, ECO:0000269\|PubMed:20412057, ECO:0000269\|PubMed:20639877, ECO:0000269\|PubMed:23583642, ECO:0000269\|PubMed:23583643, ECO:0000269\|PubMed:23663784, ECO:0000269\|PubMed:25026077, ECO:0000269\|PubMed:25282160, ECO:0000269\|PubMed:25697406, ECO:0000269\|PubMed:26000482, ECO:0000269\|PubMed:27010430, ECO:0000269\|PubMed:29244194}.


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:0000250\|UniProtKB:Q5TC82};
Pathway:		Protein modification; protein ubiquitination. {ECO:0000250\|UniProtKB:Q5TC82}.
Subunit:		Interacts with DDX6 and EDC4 (PubMed:20639877, PubMed:23583643). Interacts with CCR4-NOT deadenylase complex (PubMed:23663784). Interacts with RC3H1; the interaction is RNA independent (PubMed:25697406). {ECO:0000269\|PubMed:20639877, ECO:0000269\|PubMed:23583643, ECO:0000269\|PubMed:23663784, ECO:0000269\|PubMed:25697406}.
Subcellular location:		Cytoplasm, P-body {ECO:0000269\|PubMed:15917799, ECO:0000269\|PubMed:20412057, ECO:0000269\|PubMed:20639877, ECO:0000269\|PubMed:23583642, ECO:0000269\|PubMed:26000482}. Cytoplasmic granule {ECO:0000269\|PubMed:26000482}. Note=During stress, such as that induced by arsenite treatment, localizes to cytosolic stress granules (PubMed:26000482). Localization to stress granules, but not to P- bodies, depends upon the RING-type zinc finger. ICOS repression may correlate with the localization to P-bodies, not to stress granules (PubMed:20639877). {ECO:0000269\|PubMed:20639877, ECO:0000269\|PubMed:26000482}.
Tissue specificity:		Widely expressed, with highest levels in lymph node and thymus and slightly lesser amounts in brain, lung, and spleen (at protein level) (PubMed:23583643). Very weak expression in heart, muscle, and kidney (at protein level) (PubMed:23583643). Expressed in CD4(+) helper T-cells (at protein level) (PubMed:29244194, PubMed:15917799, PubMed:23583643). {ECO:0000269\|PubMed:15917799, ECO:0000269\|PubMed:23583643, ECO:0000269\|PubMed:29244194}.
Domain:		The ROQ region is required for CDE RNA-binding (PubMed:27010430, PubMed:25026077, PubMed:23663784). Has 2 separate RNA-binding sites, one for CDE RNA and the other for dsRNA, both sites are important for mRNA decay (By similarity). ADE RNA-binding involves an extended binding surface on the ROQ region with a number of additional residues compared with the CDE RNA (PubMed:27010430). It may also be involved in localization to stress granules (PubMed:20412057, PubMed:23583642). {ECO:0000250\|UniProtKB:Q5TC82, ECO:0000269\|PubMed:20412057, ECO:0000269\|PubMed:23583642, ECO:0000269\|PubMed:23663784, ECO:0000269\|PubMed:25026077, ECO:0000269\|PubMed:27010430}.
Domain:		The RING-type zinc finger may be required for proper localization to stress granules, but not to P-bodies. {ECO:0000269\|PubMed:23583642}.
Domain:		HEPN (higher eukaryotes and prokaryotes nucleotide-binding) are observed in both N- and C-terminal sides of ROQ domain with 3D structure even if they are poredcted on the basis of sequence. {ECO:0000269\|PubMed:25697406}.
Ptm:		Proteolytically cleaved after Arg-510 and Arg-579 by MALT1 in activated CD4(+) T cells; cleavage at Arg-510 and Arg-579 is critical for promoting RC3H1 degradation in response to T-cell receptor (TCR) stimulation, and hence is necessary for prolonging the stability of a set of mRNAs controlling Th17 cell differentiation. {ECO:0000269\|PubMed:25282160}.
Disruption phenotype:		Mutant animals are born at Mendelian ratio, but die within 6 hours after birth. They displayed a curly tail and malformations of the caudal spinal column. Lethality can be rescued by changing the genetic background from C57BL/6 to outbred CD1, which allows about 4% of the animals to survive to adulthood. These animals display enlarged spleens with a trend toward increased numbers of eosinophils and monocytic/macrophage populations, dramatic and selective expansion of CD8(+) effector-like T-cells. Splenic follicular organization is normal, and the numbers of CD4(+) T-cell subtypes and B-cells are not significantly altered. No spontaneous germinal center formation, autoantibody production, nor autoimmune tissue damage. Ablation of Rc3h1 gene in the T lineage leads to elevated ICOS levels and expansion of effector CD8(+) T-cells, but not autoimmunity (PubMed:21844204). Mice lacking both Rc3h1 and Rc3h2 genes in CD4(+) T- cells develop lymphadenopathy and splenomegaly with increased spleen weight and cellularity, already at young age. They show a prominent lung pathology with a progressive reduction in the alveolar space concomitant with inflammation. They show an average survival of 130 days. CD4(+) T-cells of these mutants show a pronounced bias toward Th17 differentiation (PubMed:21844204, PubMed:23583643). {ECO:0000269\|PubMed:21844204, ECO:0000269\|PubMed:23583643}.
Miscellaneous:		Treatment of C57BL/6 males with ethylnitrosourea led to the identification of the sanroque mouse strain. The causative mutation in sanroque appears to be RC3H1 Arg-199. Homozygous sanroque mice develop high titers of autoantibodies and display excessive numbers of follicular helper T-cells and germinal centers with pattern of pathology consistent with lupus (PubMed:15917799). Sanroque mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Extensive cytokine dysregulation resulting in both over- expression and under-expression of chemotactic cytokines occurs in the ileum, the region most prone to the development of inflammation in sanroque mice (PubMed:23451046). They show up-regulation of expression of at least 15 miRNAs in T cells (PubMed:25697406). The lack of compensation of RC3H1 defects by the RC3H2 paralog in sanroque mice may be due to the fact that the mutated protein may retain its scaffolding position within RNA granules, preventing RC3H2 to access mRNAs to be regulated (PubMed:23583642). {ECO:0000269\|PubMed:25697406, ECO:0000305\|PubMed:15917799, ECO:0000305\|PubMed:23451046, ECO:0000305\|PubMed:23583642}.
Sequence caution:		Sequence=BAD32613.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};