Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Aug;24(4):364-78.
doi: 10.1016/j.coi.2012.04.011. Epub 2012 May 30.

Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes

Stephanie Boisson-Dupuis  1 , Xiao-Fei Kong, Satoshi Okada, Sophie Cypowyj, Anne Puel, Laurent Abel, Jean-Laurent Casanova
Affiliations
Review

Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes

Stephanie Boisson-Dupuis et al. Curr Opin Immunol. 2012 Aug.

Abstract

The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The STAT1 cycle: signaling pathway and recycling. Schematic diagram of STAT1 activation and de-activation following IFN-γ stimulation. Following the binding of the cytokine to its receptor, a series of tyrosine phosphorylation events (red circles) occur: first the JAKs autophosphorylate and transphosphorylate each other; they then phosphorylate the intracellular part of the receptor, creating a docking site for STAT1. Recruited STAT1 are also phosphorylated by the JAKs, leading to their removal from the receptor, dimerization and translocation to the nucleus to modulate target gene expression. STAT1 dephosphorylation occurs in the nucleus and STATs are then exported back to the cytoplasm.
Figure 2
Figure 2
Representation of the human STAT1 gene and of the domains of the corresponding protein, with key residues and morbid mutations indicated. The human STAT1α isoform is shown, with its known pathogenic mutations. Coding exons are numbered with roman numerals and delimited by a vertical bar. Regions corresponding to the coiled-coil domain (CC), DNA-binding domain (DNA-B), linker domain (L), SH2 domain (SH2), tail segment domain (TS), and transactivator domain (TA) are indicated, together with their amino-acid boundaries, and are delimited by bold lines. Tyr701 (pY) and Ser727 (pS) are indicated. Mutations in green are dominant and associated with partial STAT1 deficiency and MSMD. Mutations in brown are recessive and associated with complete STAT1 deficiency and intracellular and viral diseases. Mutations in blue are recessive and associated with partial STAT1 deficiency and mild intracellular and/or viral disease. Mutations in red are dominant and associated with gain-of-activity of STAT1 and CMCD.
Figure 3
Figure 3
Schematic diagram of the role of STAT1 in antiviral and anti-mycobacterial immunity. Schematic representation of the STAT1-dependent signaling pathways in response to IL-27, IFN-γ, IFN-α/β and IFN-λ. In humans, STAT1-GAF dependent IFN-γ immunity is crucial for protection against mycobacteria (and other intramacrophagic microbes), and a role of STAT1-GAF-dependent IL-27 immunity in this process cannot be excluded. STAT1-ISGF3 dependent IFN-α/β immunity is crucial for protection against viruses (mainly herpes viruses), and a role of STAT1-ISGF3-dependent IFN-λ immunity cannot be excluded.
Figure 4
Figure 4
Schematic diagrams of the role of STAT1 in antimycobacterial, antiviral and antifungal immunity. In the three panels, proteins for which mutations in the corresponding genes have been identified and associated with MSMD, HSE and CMC, respectively, are shown in blue. STAT1 is shown in red. Top panel: The phagocytosis of mycobacteria leads to cytokine production and cooperation between phagocytes/dendritic cells and NK/T cells. The IL-12/23/IFN-γ loop, the CD40/CD40L pathway and the oxidative burst (mediated by CYBB, a component of NADPH oxidase) are crucial for protective immunity to mycobacteria in humans. STAT1 deficiency is associated with an impaired IFN-γ response. Middle panel: The recognition of dsRNA by TLR3 induces activation of the IRF-3 and NF-kB pathways via TRIF, leading to IFN-α/-β and/or IFN-λ production. TLR3, UNC-93B, TRIF, TRAF3, TBK1 and NEMO deficiencies are associated with impaired IFN-α/-β and/or IFN-λ production, particularly during herpes virus infection. The binding of IFN-α/-β or IFN-λ to its receptor induces the phosphorylation of JAK1 and TYK2, activating the signal transduction proteins STAT1, STAT2 and IRF9. This complex is translocated as a heterotrimer to the nucleus, where it acts as a transcriptional activator, binding to specific DNA response elements in the promoter region of IFN-inducible genes. STAT1 deficiency is associated with impaired IFN-α, IFN-β and IFN-λ responses. Bottom panel: Following the recognition of C. albicans, the CARD9 adaptor molecule mediates the induction of pro-inflammatory cytokine production by myeloid and epithelial cells. These pro-inflammatory cytokines, including IL-6 and IL-23, activate T lymphocytes via STAT3, inducing the differentiation of these cells into IL-17-producing T cells; these cells constitute a major component of immune defenses against C. albicans. Gain-of-function mutations in STAT1 inhibit this differentiation in response to IFN-α/β, IFN-γ, IFN-λ and IL-27 or the impairment of normal IL-6, IL-21 and/or IL-23 signaling, through an as yet undetermined mechanism.
Figure 5
Figure 5
Clinical consequences of low or high levels of STAT1 activity. A narrow range of STAT1 activity should be maintained to ensure health. Biallelic and even monoallelic loss-of-function (LOF) alleles, including not only null but also hypomorphic alleles, confer a predisposition to mycobacterial disease, owing to impaired IFN-γ immunity. The concomitant impairment of IFN-α/β and IFN-λ signaling further predisposes patients to viral illnesses. The severity of the clinical phenotype depends on the severity of the cellular phenotype. The impact of IL-27 hyporesponsiveness is unclear. By contrast, heterozygosity for gain-of-function (GOF) alleles owing to a gain of phosphorylation through a loss of nuclear dephosphorylation, predisposes patients to chronic mucocutaneous candidiasis (CMC) and autoimmunity (typically thyroiditis and, more rarely, other conditions, such as systemic lupus erythematosus). The mechanism underlying CMC involves an impairment of the development of IL-17 T cells, owing to enhanced STAT1-dependent responses to the IL-17 inhibitors IFN-γ, IFN-α/β, IFN-λ and IL-27, or weak STAT3-dependent responses, owing to enhanced STAT1-dependent responses to the IL-17 inducers IL-6, IL-21, and IL-23. The mechanism underlying autoimmunity probably involves enhanced IFN-α/β responses.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dale T.C., Imam A.M., Kerr I.M., Stark G.R. Rapid activation by interferon alpha of a latent DNA-binding protein present in the cytoplasm of untreated cells. Proc Natl Acad Sci USA. 1989;86:1203–1207. - PMC - PubMed
    1. Levy D.E., Kessler D.S., Pine R., Darnell J.E., Jr. Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev. 1989;3:1362–1371. - PubMed
    1. Casanova J.L., Holland S.M., Notarangelo L.D. Inborn errors of human JAKs & STATs. Immunity. 2012;36:515–528. - PMC - PubMed
    1. Schindler C., Fu X.Y., Improta T., Aebersold R., Darnell J.E., Jr. Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci USA. 1992;89:7836–7839. - PMC - PubMed
    1. Darnell J.E., Jr., Kerr I.M., Stark G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–1421. - PubMed

Publication types

Substances