Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy

Abstract

STAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2.

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

“…STAT2 plays a ying/yang role in type 1 IFN signalling. Thus, it is responsible for not only inducing, but also restraining, responses elicited via IFNαR1/2 complexes [ 110 ]. This regulatory role of STAT2 is mediated by binding to and recruiting USP18 to IFNαR2, which then prevents further recruitment of JAKs to type 1 IFN receptors, thereby attenuating IFNα signalling [ 110 ].…”

“…Thus, it is responsible for not only inducing, but also restraining, responses elicited via IFNαR1/2 complexes [110]. This regulatory role of STAT2 is mediated by binding to and recruiting USP18 to IFNαR2, which then prevents further recruitment of JAKs to type 1 IFN receptors, thereby attenuating IFNα signalling [110]. Bi-allelic variants in STAT2 that specifically affect amino acid R148 (STAT2 R148Q/W ) have now been reported [79,80].…”

A Case Study to Dissect Immunity to SARS-CoV-2 in a Neonate Nonhuman Primate Model

“…MX1 and IFIT1 were maintained at DPI 12 and 35, unlike the other genes, which decreased at DPI 12, except for IFI35 and IRF3. Finally, we identified confident interactions (at least 4 differently colored lines) between STAT2, TYK2, IRF3, MX1, ISG15, IFIT1, IFIT2, IFIT3, and IFI35 ( Figure 4D ), where STAT2 seems to be the key signal transducer and the transcription activator of some IFN-associated genes ( 48 ).…”

Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2

“…Cul1 also belongs to the Cullin family of large, helix-rich scaffold proteins [ 51 , 52 ], each of which forms specific E3 ligase complexes. Cul4 (Cullin4), for example, is a 759 aa long polypeptide that associates with DDB1 and Roc1 to form the DDB–Cul4–Roc1 ligase complex [ 51 , 52 , 53 , 54 ], important for histone methylation [ 53 ] and cellular DNA repair [ 31 , 48 ] and also for STAT degradation in paramyxovirus-infected cells ( Section 2.3.2 ). Another subclass of E3 ligase complex that is important for STAT2 degradation by pneumoviral nonstructural proteins ( Section 2.3.3 ) is the elongin C–Cullin–SOCS (ECS) box-type ligases that include the Von Hippel–Landau tumor suppressor protein and the suppressor of cytokine signaling (SOCS)-family proteins [ 51 , 55 , 56 ].…”

“…Such reports include but are not limited to the early observation of enhanced VSV virulence in KO (STAT2 –/– ) mice [ 26 ], increased pathogenesis of Rift Valley fever virus [ 27 ] and Crimean-Congo hemorrhagic fever virus [ 28 ], and increased dissemination of SARS-CoV-2 in STAT2 KO hamsters [ 29 ]. In human subjects, heterozygous carriers of STAT2 null mutations are clinically unaffected; however, those with complete loss of STAT2 function showed the interesting phenotype of severe viral disease from live-attenuated virus vaccines, such as those for measles, mumps, and rubella (MMR) and varicella zoster virus [ 30 , 31 ]. Finally, for many viruses, STAT2 of the host has been shown to determine host specificity of the virus, such that these viruses cause disease in humans only, as detailed later for individual viruses.…”