UniProt functional annotation for Q14258



	UniProt functional annotation for Q14258

UniProt code: Q14258.

Organism: Homo sapiens (Human).

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

Function: Functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase (PubMed:16352599). Involved in innate immune defense against viruses by mediating ubiquitination of DDX58 and IFIH1 (PubMed:17392790, PubMed:30193849). Mediates 'Lys-63'-linked polyubiquitination of the DDX58 N-terminal CARD-like region and may play a role in signal transduction that leads to the production of interferons in response to viral infection (PubMed:17392790, PubMed:23950712). Mediates 'Lys-63'- linked polyubiquitination of IFIH1 (PubMed:30193849). Promotes ISGylation of 14-3-3 sigma (SFN), an adapter protein implicated in the regulation of a large spectrum signaling pathway (PubMed:16352599, PubMed:17069755). Mediates estrogen action in various target organs (PubMed:22452784). Mediates the ubiquitination and subsequent proteasomal degradation of ZFHX3 (PubMed:22452784). Plays a role in promoting the restart of stalled replication forks via interaction with the KHDC3L-OOEP scaffold and subsequent ubiquitination of BLM, resulting in the recruitment and retainment of BLM at DNA replication forks (By similarity). {ECO:0000250|UniProtKB:Q61510, ECO:0000269|PubMed:16352599, ECO:0000269|PubMed:17069755, ECO:0000269|PubMed:17392790, ECO:0000269|PubMed:22452784, ECO:0000269|PubMed:23950712, ECO:0000269|PubMed:30193849}.

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:17392790};

Catalytic activity: Reaction=ATP + [ISG15] + [protein]-lysine = AMP + diphosphate + [protein]-N-ISGyllysine.; EC=6.3.2.n3; Evidence={ECO:0000269|PubMed:16352599};

Pathway: Protein modification; protein ubiquitination.

Subunit: Interacts (via SPRY domain) with DDX58 (via CARD domain). Interacts with ZFHX3. Interacts with NLRP12; this interaction reduces the E3 ubiquitin ligase TRIM25-mediated 'Lys-63'-linked DDX58 activation. Interacts with the KHDC3L/FILIA-OOEP/FLOPED scaffold complex and BLM at DNA replication forks (By similarity). {ECO:0000250|UniProtKB:Q61510, ECO:0000269|PubMed:17392790, ECO:0000269|PubMed:22452784, ECO:0000269|PubMed:23950712, ECO:0000269|PubMed:30902577}.

Subunit: (Microbial infection) Interacts (via coiled coil) with influenza A virus NS1 protein; this interaction specifically inhibits TRIM25 multimerization and TRIM25-mediated DDX58 CARD ubiquitination, thereby suppressing DDX58 signal transduction. {ECO:0000269|PubMed:19454348}.

Subunit: (Microbial infection) Interacts (via SPRY domain) with human respiratory syncytial virus (HRSV) non-structural protein 1; this interaction suppresses DDX58 ubiquitination and results in decreased interaction between DDX58 and MAVS. {ECO:0000269|PubMed:30558248}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:17392790}. Cytoplasm, Stress granule {ECO:0000269|PubMed:23950712}. Nucleus {ECO:0000250|UniProtKB:Q61510}.

Tissue specificity: Expressed in breast tumors (at protein level). Ubiquitous. {ECO:0000269|PubMed:15130519, ECO:0000269|PubMed:22452784}.

Induction: By interferons. {ECO:0000269|PubMed:16352599, ECO:0000269|PubMed:17069755}.

Domain: The RING-type zinc finger is important for ISG15 E3 ligase activity and autoISGylation. AutoISGylation negatively regulates ISG15 E3 ligase activity.

Domain: The C-terminal B30.2/SPRY domain interacts with the first N- terminal CARD domain of DDX58.

Ptm: Auto-ISGylated. {ECO:0000269|PubMed:17222803}.

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:		Functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase (PubMed:16352599). Involved in innate immune defense against viruses by mediating ubiquitination of DDX58 and IFIH1 (PubMed:17392790, PubMed:30193849). Mediates 'Lys-63'-linked polyubiquitination of the DDX58 N-terminal CARD-like region and may play a role in signal transduction that leads to the production of interferons in response to viral infection (PubMed:17392790, PubMed:23950712). Mediates 'Lys-63'- linked polyubiquitination of IFIH1 (PubMed:30193849). Promotes ISGylation of 14-3-3 sigma (SFN), an adapter protein implicated in the regulation of a large spectrum signaling pathway (PubMed:16352599, PubMed:17069755). Mediates estrogen action in various target organs (PubMed:22452784). Mediates the ubiquitination and subsequent proteasomal degradation of ZFHX3 (PubMed:22452784). Plays a role in promoting the restart of stalled replication forks via interaction with the KHDC3L-OOEP scaffold and subsequent ubiquitination of BLM, resulting in the recruitment and retainment of BLM at DNA replication forks (By similarity). {ECO:0000250\|UniProtKB:Q61510, ECO:0000269\|PubMed:16352599, ECO:0000269\|PubMed:17069755, ECO:0000269\|PubMed:17392790, ECO:0000269\|PubMed:22452784, ECO:0000269\|PubMed:23950712, ECO:0000269\|PubMed:30193849}.


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:17392790};
Catalytic activity:		Reaction=ATP + [ISG15] + [protein]-lysine = AMP + diphosphate + [protein]-N-ISGyllysine.; EC=6.3.2.n3; Evidence={ECO:0000269\|PubMed:16352599};
Pathway:		Protein modification; protein ubiquitination.
Subunit:		Interacts (via SPRY domain) with DDX58 (via CARD domain). Interacts with ZFHX3. Interacts with NLRP12; this interaction reduces the E3 ubiquitin ligase TRIM25-mediated 'Lys-63'-linked DDX58 activation. Interacts with the KHDC3L/FILIA-OOEP/FLOPED scaffold complex and BLM at DNA replication forks (By similarity). {ECO:0000250\|UniProtKB:Q61510, ECO:0000269\|PubMed:17392790, ECO:0000269\|PubMed:22452784, ECO:0000269\|PubMed:23950712, ECO:0000269\|PubMed:30902577}.
Subunit:		(Microbial infection) Interacts (via coiled coil) with influenza A virus NS1 protein; this interaction specifically inhibits TRIM25 multimerization and TRIM25-mediated DDX58 CARD ubiquitination, thereby suppressing DDX58 signal transduction. {ECO:0000269\|PubMed:19454348}.
Subunit:		(Microbial infection) Interacts (via SPRY domain) with human respiratory syncytial virus (HRSV) non-structural protein 1; this interaction suppresses DDX58 ubiquitination and results in decreased interaction between DDX58 and MAVS. {ECO:0000269\|PubMed:30558248}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:17392790}. Cytoplasm, Stress granule {ECO:0000269\|PubMed:23950712}. Nucleus {ECO:0000250\|UniProtKB:Q61510}.
Tissue specificity:		Expressed in breast tumors (at protein level). Ubiquitous. {ECO:0000269\|PubMed:15130519, ECO:0000269\|PubMed:22452784}.
Induction:		By interferons. {ECO:0000269\|PubMed:16352599, ECO:0000269\|PubMed:17069755}.
Domain:		The RING-type zinc finger is important for ISG15 E3 ligase activity and autoISGylation. AutoISGylation negatively regulates ISG15 E3 ligase activity.
Domain:		The C-terminal B30.2/SPRY domain interacts with the first N- terminal CARD domain of DDX58.
Ptm:		Auto-ISGylated. {ECO:0000269\|PubMed:17222803}.