Alt. symbols: STAT113

Approved name: signal transducer and activator of transcription 2
Alt. names: signal transducer and activator of transcription 2, 113kD, signal transducer and activator of transcription 2, 113kDa

Location: 12q13.3: 56341597 - 56360203 (-)
Gene type: protein_coding, 42 transcripts.

Scores: LoFtool: 0.154000 | pLI: 0.04109474 | LOEUF: 0.319

HGNC: 11363

NCBI: 6773, RefSeq: NG_046314.1

Ensembl: ENSG00000170581.15

LRG_1329 | Status: public

OMIM: 600556

Expression | ProteinAtlas

STAT2 encodes a member of the STAT (Signal transducer and activator of transcription) family of transcription factors, which mediate signaling by type I interferons (IFNs) IFN-alpha and IFN-beta. Following type I IFN binding to cell surface receptors, Jak kinases TYK2 and JAK1 are activated, leading to STAT1 and STAT2 recruitment and tyrosine phosphorylation. The phosphorylated STATs then dimerize and associate with IRF9/ISGF3G to form the ISGF3 transcription factor complex, which translocates to the nucleus to bind IFN-stimulated response elements (ISRE) and activate IFN-stimulated genes (PMID: 9020188, 23391734). STAT2 plays an additional negative feedback regulatory role in type I IFN signaling by recruiting USP18 to the type I IFN receptor subunit IFNAR2 to dampen the response to type I IFNs (PMID: 28165510). STAT2 has also been implicated as a regulator of mitochondrial fission by modulating the serine phosphorylation of DNM1L to control its GTPase activity (PMID: 26122121, 23391734, 9020188).

Biallelic STAT2 LOF and GOF mutations are both associated with autosomal recessive IEIs - the former with a primary immunodeficiency syndrome characterized by increased susceptibility to viral infections and adverse reactions to vaccination [OMIM: 616636] (PMID: 23391734) and the latter with severe early-onset type I IFNopathy [OMIM: 618886]. Reported patients with the latter were children of consanguineous parents who carried homozygous missense mutations affecting the same Arg148 residue withi n the STAT2/USP18 interacting domain, resulting in impaired STAT2 binding to and recruitment of USP18 to suppress IFNAR2-mediated inflammation (PMID: 31836668, 32092142). This manifests clinically as severe early onset neuroinflammation featuring apneic episodes, seizures, progressive intracranial calcification, parenchymal hemorrhage, abnormal cerebral white matter, and brainstem and cerebellar atrophy, along with evidence of systemic, multi-organ inflammation, including skin ulcerations, recurrent fevers, hepatosplenomegaly, cytopenias, and kidney injury. Adaptive immunophenotyping was largely normal, but one patient showed elevated T cell and low NK cell and monocyte frequencies. All patients showed significant elevations of a type I IFN gene signature, and some were additionally found to show elevated CD169 expression on monocytes and dendritic cells. [Load More]