Top

Published in:

01-10-2021 | Interferon | CME Review

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

Authors: Christopher James Arthur Duncan, Sophie Hambleton

Published in: Journal of Clinical Immunology | Issue 7/2021

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.

Uggenti C, et al. Self-awareness: nucleic acid-driven inflammation and the type I interferonopathies. Annu Rev Immunol. 2019;37:247–67.PubMedCrossRef

Moens L, Meyts I. Recent human genetic errors of innate immunity leading to increased susceptibility to infection. Curr Opin Immunol. 2020;62:79–90.PubMedCrossRef

Duncan CJA, et al. Genetic lesions of type I interferon signalling in human antiviral immunity. Trends Genet. 2021;37(1):46–58.PubMedCrossRef

Zhang Q et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570

Reich N, et al. Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc Natl Acad Sci U S A. 1987;84(18):6394–8.PubMedPubMedCentralCrossRef

Levy DE, et al. Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 1988;2(4):383–93.PubMedCrossRef

Fu XY, et al. The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992;89(16):7840–3.PubMedPubMedCentralCrossRef

Leung S, et al. Role of STAT2 in the alpha interferon signaling pathway. Mol Cell Biol. 1995;15(3):1312–7.PubMedPubMedCentralCrossRef

Park C, et al. Immune response in Stat2 knockout mice. Immunity. 2000;13(6):795–804.PubMedCrossRef

10.

Meraz MA, et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996;84(3):431–42.PubMedCrossRef

11.

Muller U, et al. Functional role of type I and type II interferons in antiviral defense. Science. 1994;264(5167):1918–21.PubMedCrossRef

12.

Muller M, et al. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993;366(6451):129–35.PubMedCrossRef

13.

Velazquez L, et al. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992;70(2):313–22.PubMedCrossRef

14.

Decker T, et al. Cytoplasmic activation of GAF, an IFN-gamma-regulated DNA-binding factor. EMBO J. 1991;10(4):927–32.PubMedPubMedCentralCrossRef

15.

Platanitis E, et al. A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription. Nat Commun. 2019;10(1):2921.PubMedPubMedCentralCrossRef

16.

Cheon H, et al. IFNbeta-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J. 2013;32(20):2751–63.PubMedPubMedCentralCrossRef

17.

Wang W, et al. Unphosphorylated ISGF3 drives constitutive expression of interferon-stimulated genes to protect against viral infections. Sci Signal. 2017;10(476):eaah4248.PubMedCrossRef

18.

Blaszczyk K, et al. The unique role of STAT2 in constitutive and IFN-induced transcription and antiviral responses. Cytokine Growth Factor Rev. 2016;29:71–81.PubMedCrossRef

19.

Hambleton S, et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc Natl Acad Sci U S A. 2013;110(8):3053–8.PubMedPubMedCentralCrossRef

20.

Shahni R, et al. Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission. Brain. 2015;138(Pt 10):2834–46.PubMedPubMedCentralCrossRef

21.

Moens L, et al. A novel kindred with inherited STAT2 deficiency and severe viral illness. J Allergy Clin Immunol. 2017;139(6):1995-1997 e9.PubMedCrossRef

22.

Alosaimi MF, et al. A novel variant in STAT2 presenting with hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol. 2019;144(2):611-613 e3.PubMedPubMedCentralCrossRef

23.

Freij B et al. Life-threatening influenza, haemophagocytic lymphohistiocytosis and probable vaccine strain varicella in a novel case of homozygous STAT2 deficiency. Front Immunol. 2021;11:624415.

24.

Steen HC, et al. Identification of STAT2 serine 287 as a novel regulatory phosphorylation site in type I interferon-induced cellular responses. J Biol Chem. 2013;288(1):747–58.PubMedCrossRef

25.

Wang Y, et al. Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387. EMBO J. 2017;36(2):202–12.PubMedCrossRef

26.

Steen HC, et al. Phosphorylation of STAT2 on serine-734 negatively regulates the IFN-alpha-induced antiviral response. J Cell Sci. 2016;129(22):4190–9.PubMedPubMedCentral

27.

Wang Y, et al. A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses. Cell Res. 2021;31(2):206–18.PubMedCrossRef

28.

Tang X, et al. Acetylation-dependent signal transduction for type I interferon receptor. Cell. 2007;131(1):93–105.PubMedCrossRef

29.

Frahm T, et al. IFN-type-I-mediated signaling is regulated by modulation of STAT2 nuclear export. J Cell Sci. 2006;119(Pt 6):1092–104.PubMedCrossRef

30.

Rengachari S, et al. Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function. Proc Natl Acad Sci U S A. 2018;115(4):E601–9.PubMedPubMedCentralCrossRef

31.

Martinez-Moczygemba M, et al. Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3. J Biol Chem. 1997;272(32):20070–6.PubMedCrossRef

32.

Ho J, et al. STAT2 Is a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways. PLoS Biol. 2016;14(10):e2000117.PubMedPubMedCentralCrossRef

33.

Stancato LF, et al. Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation. J Biol Chem. 1996;271(8):4134–7.PubMedCrossRef

34.

Li X, et al. Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling. Mol Cell Biol. 1997;17(4):2048–56.PubMedPubMedCentralCrossRef

35.

Bluyssen HA, Levy DE. Stat2 is a transcriptional activator that requires sequence-specific contacts provided by stat1 and p48 for stable interaction with DNA. J Biol Chem. 1997;272(7):4600–5.PubMedCrossRef

36.

Qureshi SA, et al. Function of Stat2 protein in transcriptional activation by alpha interferon. Mol Cell Biol. 1996;16(1):288–93.PubMedPubMedCentralCrossRef

37.

Chowdhury FZ, Farrar JD. STAT2: a shape-shifting anti-viral super STAT. JAKSTAT. 2013;2(1):e123633.

38.

Park C, et al. Murine STAT2 is uncharacteristically divergent. Nucleic Acids Res. 1999;27(21):4191–9.PubMedPubMedCentralCrossRef

39.

Paulson M, et al. Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J Biol Chem. 1999;274(36):25343–9.PubMedCrossRef

40.

Ashour J, et al. Mouse STAT2 restricts early dengue virus replication. Cell Host Microbe. 2010;8(5):410–21.PubMedPubMedCentralCrossRef

41.

Grant A, et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe. 2016;19(6):882–90.PubMedPubMedCentralCrossRef

42.

Joyce MA, et al. HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: up-regulation of PDLIM2 suppresses the innate immune response. PLoS Pathog. 2019;15(8):e1007949.PubMedPubMedCentralCrossRef

43.

Ulane CM, Horvath CM. Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components. Virology. 2002;304(2):160–6.PubMedCrossRef

44.

Precious B, et al. In vitro and in vivo specificity of ubiquitination and degradation of STAT1 and STAT2 by the V proteins of the paramyxoviruses simian virus 5 and human parainfluenza virus type 2. J Gen Virol. 2005;86(Pt 1):151–8.PubMedCrossRef

45.

Xu X, et al. Respiratory syncytial virus NS1 protein degrades STAT2 by inducing SOCS1 expression. Intervirology. 2014;57(2):65–73.PubMedCrossRef

46.

Le VTK, et al. Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation. J Gen Virol. 2008;89(Pt 10):2416–26.PubMedCrossRef

47.

Wang B, et al. Structural basis for STAT2 suppression by flavivirus NS5. Nat Struct Mol Biol. 2020;27(10):875–85.PubMedPubMedCentralCrossRef

48.

Rogers MC, et al. STAT2 limits host species specificity of human metapneumovirus. Viruses. 2020;12(7):724.PubMedCentralCrossRef

49.

Nan J, et al. IRF9 and unphosphorylated STAT2 cooperate with NF-kappaB to drive IL6 expression. Proc Natl Acad Sci U S A. 2018;115(15):3906–11.PubMedPubMedCentralCrossRef

50.

Arimoto KI, et al. STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nat Struct Mol Biol. 2017;24(3):279–89.PubMedPubMedCentralCrossRef

51.

Malakhova OA, et al. UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. EMBO J. 2006;25(11):2358–67.PubMedPubMedCentralCrossRef

52.

Francois-Newton V, et al. USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon alpha response. PLoS One. 2011;6(7):e122200.CrossRef

53.

Goldmann T, et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 2015;34(12):1612–29.PubMedPubMedCentralCrossRef

54.

Meuwissen ME, et al. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med. 2016;213(7):1163–74.PubMedPubMedCentralCrossRef

55.

Alsohime F, et al. JAK inhibitor therapy in a child with inherited USP18 deficiency. N Engl J Med. 2020;382(3):256–65.PubMedPubMedCentralCrossRef

56.

Duncan CJA, et al. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Sci Immunol. 2019;4(42):eaav7501.PubMedPubMedCentralCrossRef

57.

Gruber C, et al. Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy. J Exp Med. 2020;217(5):e20192319.PubMedPubMedCentralCrossRef

58.

Hernandez N, et al. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines. J Exp Med. 2019;216(9):2057–70.PubMedPubMedCentralCrossRef

59.

Bastard P, et al. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J Exp Med. 2021;218(4):e20202486.PubMedCrossRefPubMedCentral

60.

Zhang SY, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–7.PubMedCrossRef

61.

Andersen LL, et al. Functional IRF3 deficiency in a patient with herpes simplex encephalitis. J Exp Med. 2015;212(9):1371–9.PubMedPubMedCentralCrossRef

62.

Israel L, et al. Human adaptive immunity rescues an inborn error of innate immunity. Cell. 2017;168(5):789-800 e10.PubMedPubMedCentralCrossRef

63.

Picard C, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003;299(5615):2076–9.PubMedCrossRef

64.

von Bernuth H, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321(5889):691–6.CrossRef

65.

Gopal R, et al. STAT2 Signaling regulates macrophage phenotype during influenza and bacterial super-infection. Front Immunol. 2018;9:2151.PubMedPubMedCentralCrossRef

66.

Alazawi W, et al. Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis. Proc Natl Acad Sci U S A. 2013;110(21):8656–61.PubMedPubMedCentralCrossRef

67.

Karaghiosoff M, et al. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat Immunol. 2003;4(5):471–7.PubMedCrossRef

68.

Zhao W, et al. Stat2-dependent regulation of MHC class II expression. J Immunol. 2007;179(1):463–71.PubMedCrossRef

69.

Katz U, et al. Update on intravenous immunoglobulins (IVIg) mechanisms of action and off- label use in autoimmune diseases. Curr Pharm Des. 2011;17(29):3166–75.PubMedCrossRef

70.

Group, R.C. , et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693–704.CrossRef

71.

Investigators R-C, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;384(16):1491–502.CrossRef

72.

Naviglio S, et al. Long-term survival after hematopoietic stem cell transplantation for complete STAT1 deficiency. J Clin Immunol. 2017;37(7):701–6.PubMedCrossRef

73.

Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15(7):429–40.PubMedCrossRef

74.

Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984;15(1):49–54.PubMedCrossRef

75.

Lochte S, et al. Live cell micropatterning reveals the dynamics of signaling complexes at the plasma membrane. J Cell Biol. 2014;207(3):407–18.PubMedPubMedCentralCrossRef

76.

Sarasin-Filipowicz M, et al. Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43. Mol Cell Biol. 2009;29(17):4841–51.PubMedPubMedCentralCrossRef

77.

Larner AC, et al. Transcriptional induction by interferon. New protein(s) determine the extent and length of the induction. J Biol Chem. 1986;261(1):453–9.PubMedCrossRef

78.

Cavaco BM, et al. Homozygous calcium-sensing receptor polymorphism R544Q presents as hypocalcemic hypoparathyroidism. J Clin Endocrinol Metab. 2018;103(8):2879–88.PubMedCrossRef

79.

Drutman SB, et al. Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis. Proc Natl Acad Sci U S A. 2019;116(38):19055–63.PubMedPubMedCentralCrossRef

80.

Liu L, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48.PubMedPubMedCentralCrossRef

81.

van de Veerdonk FL, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365(1):54–61.PubMedCrossRef

82.

Flanagan SE, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46(8):812–4.PubMedPubMedCentralCrossRef

83.

Milner JD, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591–9.PubMedPubMedCentralCrossRef

84.

Del Bel KL, et al. JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. J Allergy Clin Immunol. 2017;139(6):2016-2020 e5.PubMedCrossRef

85.

Gruber CN, et al. Complex autoinflammatory syndrome unveils fundamental principles of JAK1 kinase transcriptional and biochemical function. Immunity. 2020;53(3):672-684 e11.PubMedPubMedCentralCrossRef

Title: Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy
Authors: Christopher James Arthur Duncan
Sophie Hambleton
Publication date: 01-10-2021
Publisher: Springer US
Keyword: Interferon
Published in: Journal of Clinical Immunology / Issue 7/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-021-01118-z

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2021

Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy

Curative Treatment of POMP-Related Autoinflammation and Immune Dysregulation (PRAID) by Hematopoietic Stem Cell Transplantation

ALPK1 Gene Mutations Drive Autoinflammation with Ectodermal Dysplasia and Progressive Vision Loss

Deficiency of Adenosine Deaminase 2—a Monogenic Cause of Wunderlich Syndrome

BCG Vaccine–Associated Complications in Patients with PTEN Hamartoma Tumor Syndrome

Achromobacter xylosoxidans Pneumonia in a Young Child with Chronic Granulomatous Disease—a Case-Based Review

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page