UniProt functional annotation for Q8C6L5



	UniProt functional annotation for Q8C6L5

UniProt code: Q8C6L5.

Organism: Mus musculus (Mouse).

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

Function: Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and plays a key role in innate immunity (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768, PubMed:28214358). Catalysis involves both the formation of a 2',5' phosphodiester linkage at the GpA step and the formation of a 3',5' phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p] (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768, PubMed:28214358). Acts as a key cytosolic DNA sensor, the presence of double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that triggers the immune responses (PubMed:23722158, PubMed:28363908, PubMed:28314590). Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production (PubMed:23722158, PubMed:28363908, PubMed:28314590). Preferentially binds long dsDNA (around 45 bp) and forms ladder-like networks that function cooperatively to stabilize individual cGAS-dsDNA complexes (PubMed:28902841). Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm (PubMed:23258413, PubMed:23647843, PubMed:23722158). Also acts as an innate immune sensor of infection by retroviruses by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:23929945). Detection of retroviral reverse-transcribed DNA in the cytosol may be indirect and be mediated via interaction with PQBP1, which directly binds reverse-transcribed retroviral DNA (By similarity). Also detects the presence of DNA from bacteria (By similarity). cGAMP can be transferred from producing cells to neighboring cells through gap junctions, leading to promote TMEM173/STING activation and convey immune response to connecting cells (PubMed:24077100). cGAMP can also be transferred between cells by virtue of packaging within viral particles contributing to IFN- induction in newly infected cells in a cGAS-independent but TMEM173/STING-dependent manner (PubMed:26229117). In addition to antiviral activity, also involved in the response to cellular stresses, such as senescence, DNA damage or genome instability (PubMed:28738408, PubMed:28759028). Acts as a regulator of cellular senescence by binding to cytosolic chromatin fragments that are present in senescent cells, leading to trigger type-I interferon production via TMEM173/STING and promote cellular senescence (PubMed:28759028). Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability (PubMed:28738408). Micronuclei, which as frequently found in cancer cells, consist of chromatin surrounded by its own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, CGAS binds self-DNA exposed to the cytosol, leading to cGAMP synthesis and subsequent activation of TMEM173/STING and type-I interferon production (PubMed:28738408). Acts as a suppressor of DNA repair in response to DNA damage: translocates to the nucleus following dephosphorylation at Tyr-201 and inhibits homologous recombination repair by interacting with PARP1, the CGAS- PARP1 interaction leading to impede the formation of the PARP1-TIMELESS complex (PubMed:30356214). {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:23722158, ECO:0000269|PubMed:23929945, ECO:0000269|PubMed:24077100, ECO:0000269|PubMed:26229117, ECO:0000269|PubMed:26829768, ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:28363908, ECO:0000269|PubMed:28738408, ECO:0000269|PubMed:28759028, ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:30356214}.

Catalytic activity: Reaction=ATP + GTP = 2',3'-cGAMP + 2 diphosphate; Xref=Rhea:RHEA:42064, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:37565, ChEBI:CHEBI:143093; EC=2.7.7.86; Evidence={ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:28963528, ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30007416};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:23647843}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269|PubMed:23647843}; Note=Binds 1 Mg(2+) per subunit. Is also active with Mn(2+). {ECO:0000269|PubMed:23647843};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:29976794}; Note=Undergoes a liquid-like phase transition after binding to DNA, which is dependent on zinc. {ECO:0000250|UniProtKB:Q8N884};

Activity regulation: Nucleotidyltransferase activity is stimulated by double-stranded DNA but not RNA (By similarity). Acetylation at Lys- 372, Lys-382 and Lys-402 inhibits the cyclic GMP-AMP synthase activity (By similarity). The enzyme activity is impaired by the cleavage by CASP1 (PubMed:28314590). Strongly inhibited by compound RU.521, which is specific for mouse protein (PubMed:28963528, PubMed:30007416). {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:28963528, ECO:0000269|PubMed:30007416}.

Subunit: Monomer in the absence of DNA (PubMed:28214358). Homodimer in presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two DNA molecules (PubMed:28902841). Interacts with PQBP1 (via WW domain) (By similarity). Interacts with TRIM14; this interaction stabilizes CGAS and promotes type I interferon production (By similarity). Interacts with ZCCHC3; promoting sensing of dsDNA by CGAS (By similarity). Interacts with PARP1; interaction takes place in the nucleus and prevents the formation of the PARP1-TIMELESS complex (By similarity). {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28902841}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:30827685}; Peripheral membrane protein {ECO:0000269|PubMed:30827685}. Cytoplasm, cytosol {ECO:0000269|PubMed:23258413}. Nucleus {ECO:0000250|UniProtKB:Q8N884}. Note=In resting conditions, localizes at the cell membrane as a peripheral membrane protein by binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:30827685). Localization at the cell membrane is required to limit the recognition of self-DNA (By similarity). Following detection of double-stranded DNA (dsDNA), released from the cell membrane into the cytosol in order to signal (By similarity). Upon transfection with dsDNA forms punctate structures that co-localize with DNA and Beclin-1 (BECN1) (By similarity). Phosphorylation at Tyr-201 promotes cytosolic retention; translocates into the nucleus following dephosphorylation (By similarity). {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:30827685}.

Domain: The N-terminal part (1-146) binds unspecifically dsDNA and expand the binding and moving range of CGAS on dsDNA. Enhances the enzyme activity and activation of innate immune signaling upon cytosolic recognition of dsDNA (PubMed:28363908, PubMed:28214358, PubMed:28314590). When the N-terminal part (1-146) is missing the protein bound to dsDNA homodimerizes (PubMed:28214358). {ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:28363908}.

Ptm: Polyglutamylated by TTLL6 at Glu-272, leading to impair DNA- binding activity. Monoglutamylated at Glu-302 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6. {ECO:0000269|PubMed:26829768}.

Ptm: Cleaved by CASP1 upon DNA virus infection; the cleavage impairs cGAMP production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 during non-canonical inflammasome activation; does not cut at the same sites than CASP1 (PubMed:28314590). {ECO:0000269|PubMed:28314590}.

Ptm: Phosphorylation at Tyr-201 by BLK promotes cytosolic retention. Translocates into the nucleus following dephosphorylation at Tyr-201. {ECO:0000250|UniProtKB:Q8N884}.

Ptm: Acetylation at Lys-372, Lys-382 and Lys-402 inhibits the cyclic GMP-AMP synthase activity. Deacetylated upon cytosolic DNA challenge such as viral infections. {ECO:0000250|UniProtKB:Q8N884}.

Similarity: Belongs to the mab-21 family. {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:		Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and plays a key role in innate immunity (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768, PubMed:28214358). Catalysis involves both the formation of a 2',5' phosphodiester linkage at the GpA step and the formation of a 3',5' phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p] (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768, PubMed:28214358). Acts as a key cytosolic DNA sensor, the presence of double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that triggers the immune responses (PubMed:23722158, PubMed:28363908, PubMed:28314590). Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production (PubMed:23722158, PubMed:28363908, PubMed:28314590). Preferentially binds long dsDNA (around 45 bp) and forms ladder-like networks that function cooperatively to stabilize individual cGAS-dsDNA complexes (PubMed:28902841). Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm (PubMed:23258413, PubMed:23647843, PubMed:23722158). Also acts as an innate immune sensor of infection by retroviruses by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:23929945). Detection of retroviral reverse-transcribed DNA in the cytosol may be indirect and be mediated via interaction with PQBP1, which directly binds reverse-transcribed retroviral DNA (By similarity). Also detects the presence of DNA from bacteria (By similarity). cGAMP can be transferred from producing cells to neighboring cells through gap junctions, leading to promote TMEM173/STING activation and convey immune response to connecting cells (PubMed:24077100). cGAMP can also be transferred between cells by virtue of packaging within viral particles contributing to IFN- induction in newly infected cells in a cGAS-independent but TMEM173/STING-dependent manner (PubMed:26229117). In addition to antiviral activity, also involved in the response to cellular stresses, such as senescence, DNA damage or genome instability (PubMed:28738408, PubMed:28759028). Acts as a regulator of cellular senescence by binding to cytosolic chromatin fragments that are present in senescent cells, leading to trigger type-I interferon production via TMEM173/STING and promote cellular senescence (PubMed:28759028). Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability (PubMed:28738408). Micronuclei, which as frequently found in cancer cells, consist of chromatin surrounded by its own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, CGAS binds self-DNA exposed to the cytosol, leading to cGAMP synthesis and subsequent activation of TMEM173/STING and type-I interferon production (PubMed:28738408). Acts as a suppressor of DNA repair in response to DNA damage: translocates to the nucleus following dephosphorylation at Tyr-201 and inhibits homologous recombination repair by interacting with PARP1, the CGAS- PARP1 interaction leading to impede the formation of the PARP1-TIMELESS complex (PubMed:30356214). {ECO:0000250\|UniProtKB:Q8N884, ECO:0000269\|PubMed:23258413, ECO:0000269\|PubMed:23647843, ECO:0000269\|PubMed:23722158, ECO:0000269\|PubMed:23929945, ECO:0000269\|PubMed:24077100, ECO:0000269\|PubMed:26229117, ECO:0000269\|PubMed:26829768, ECO:0000269\|PubMed:28214358, ECO:0000269\|PubMed:28314590, ECO:0000269\|PubMed:28363908, ECO:0000269\|PubMed:28738408, ECO:0000269\|PubMed:28759028, ECO:0000269\|PubMed:28902841, ECO:0000269\|PubMed:30356214}.


Catalytic activity:		Reaction=ATP + GTP = 2',3'-cGAMP + 2 diphosphate; Xref=Rhea:RHEA:42064, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:37565, ChEBI:CHEBI:143093; EC=2.7.7.86; Evidence={ECO:0000269\|PubMed:23647843, ECO:0000269\|PubMed:28963528, ECO:0000269\|PubMed:29976794, ECO:0000269\|PubMed:30007416};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:23647843}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269\|PubMed:23647843}; Note=Binds 1 Mg(2+) per subunit. Is also active with Mn(2+). {ECO:0000269\|PubMed:23647843};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:29976794}; Note=Undergoes a liquid-like phase transition after binding to DNA, which is dependent on zinc. {ECO:0000250\|UniProtKB:Q8N884};
Activity regulation:		Nucleotidyltransferase activity is stimulated by double-stranded DNA but not RNA (By similarity). Acetylation at Lys- 372, Lys-382 and Lys-402 inhibits the cyclic GMP-AMP synthase activity (By similarity). The enzyme activity is impaired by the cleavage by CASP1 (PubMed:28314590). Strongly inhibited by compound RU.521, which is specific for mouse protein (PubMed:28963528, PubMed:30007416). {ECO:0000250\|UniProtKB:Q8N884, ECO:0000269\|PubMed:28314590, ECO:0000269\|PubMed:28963528, ECO:0000269\|PubMed:30007416}.
Subunit:		Monomer in the absence of DNA (PubMed:28214358). Homodimer in presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two DNA molecules (PubMed:28902841). Interacts with PQBP1 (via WW domain) (By similarity). Interacts with TRIM14; this interaction stabilizes CGAS and promotes type I interferon production (By similarity). Interacts with ZCCHC3; promoting sensing of dsDNA by CGAS (By similarity). Interacts with PARP1; interaction takes place in the nucleus and prevents the formation of the PARP1-TIMELESS complex (By similarity). {ECO:0000250\|UniProtKB:Q8N884, ECO:0000269\|PubMed:28214358, ECO:0000269\|PubMed:28902841}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:30827685}; Peripheral membrane protein {ECO:0000269\|PubMed:30827685}. Cytoplasm, cytosol {ECO:0000269\|PubMed:23258413}. Nucleus {ECO:0000250\|UniProtKB:Q8N884}. Note=In resting conditions, localizes at the cell membrane as a peripheral membrane protein by binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:30827685). Localization at the cell membrane is required to limit the recognition of self-DNA (By similarity). Following detection of double-stranded DNA (dsDNA), released from the cell membrane into the cytosol in order to signal (By similarity). Upon transfection with dsDNA forms punctate structures that co-localize with DNA and Beclin-1 (BECN1) (By similarity). Phosphorylation at Tyr-201 promotes cytosolic retention; translocates into the nucleus following dephosphorylation (By similarity). {ECO:0000250\|UniProtKB:Q8N884, ECO:0000269\|PubMed:30827685}.
Domain:		The N-terminal part (1-146) binds unspecifically dsDNA and expand the binding and moving range of CGAS on dsDNA. Enhances the enzyme activity and activation of innate immune signaling upon cytosolic recognition of dsDNA (PubMed:28363908, PubMed:28214358, PubMed:28314590). When the N-terminal part (1-146) is missing the protein bound to dsDNA homodimerizes (PubMed:28214358). {ECO:0000269\|PubMed:28214358, ECO:0000269\|PubMed:28314590, ECO:0000269\|PubMed:28363908}.
Ptm:		Polyglutamylated by TTLL6 at Glu-272, leading to impair DNA- binding activity. Monoglutamylated at Glu-302 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6. {ECO:0000269\|PubMed:26829768}.
Ptm:		Cleaved by CASP1 upon DNA virus infection; the cleavage impairs cGAMP production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 during non-canonical inflammasome activation; does not cut at the same sites than CASP1 (PubMed:28314590). {ECO:0000269\|PubMed:28314590}.
Ptm:		Phosphorylation at Tyr-201 by BLK promotes cytosolic retention. Translocates into the nucleus following dephosphorylation at Tyr-201. {ECO:0000250\|UniProtKB:Q8N884}.
Ptm:		Acetylation at Lys-372, Lys-382 and Lys-402 inhibits the cyclic GMP-AMP synthase activity. Deacetylated upon cytosolic DNA challenge such as viral infections. {ECO:0000250\|UniProtKB:Q8N884}.
Similarity:		Belongs to the mab-21 family. {ECO:0000305}.