2ka6

Structural highlights

Disease

[STAT1_HUMAN] Defects in STAT1 are the cause of STAT1 deficiency complete (STAT1D) [MIM:613796]. STAT1D is a disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness.^{[1] [2]} Defects in STAT1 are a cause of Mendelian susceptibility to mycobacterial disease (MSMD) [MIM:209950]; also known as familial disseminated atypical mycobacterial infection. This rare condition confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. The pathogenic mechanism underlying MSMD is the impairment of interferon-gamma mediated immunity whose severity determines the clinical outcome. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance.^{[3] [4] [5]} Defects in STAT1 are the cause of familial candidiasis type 7 (CANDF7) [MIM:614162]. A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. Note=STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin-17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643).^{[6] [7]}

Function

[CBP_MOUSE] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300 (By similarity).^{[8] [9] [10] [11]} [STAT1_HUMAN] Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated. It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.^{[12] [13] [14] [15] [16]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• CREB-binding protein

References

1. ↑ Dupuis S, Jouanguy E, Al-Hajjar S, Fieschi C, Al-Mohsen IZ, Al-Jumaah S, Yang K, Chapgier A, Eidenschenk C, Eid P, Al Ghonaium A, Tufenkeji H, Frayha H, Al-Gazlan S, Al-Rayes H, Schreiber RD, Gresser I, Casanova JL. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet. 2003 Mar;33(3):388-91. Epub 2003 Feb 18. PMID:12590259 doi:10.1038/ng1097
2. ↑ Kong XF, Ciancanelli M, Al-Hajjar S, Alsina L, Zumwalt T, Bustamante J, Feinberg J, Audry M, Prando C, Bryant V, Kreins A, Bogunovic D, Halwani R, Zhang XX, Abel L, Chaussabel D, Al-Muhsen S, Casanova JL, Boisson-Dupuis S. A novel form of human STAT1 deficiency impairing early but not late responses to interferons. Blood. 2010 Dec 23;116(26):5895-906. doi: 10.1182/blood-2010-04-280586. Epub 2010, Sep 14. PMID:20841510 doi:10.1182/blood-2010-04-280586
3. ↑ Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J, Holland SM, Schreiber RD, Casanova JL. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science. 2001 Jul 13;293(5528):300-3. PMID:11452125 doi:10.1126/science.1061154
4. ↑ Chapgier A, Boisson-Dupuis S, Jouanguy E, Vogt G, Feinberg J, Prochnicka-Chalufour A, Casrouge A, Yang K, Soudais C, Fieschi C, Santos OF, Bustamante J, Picard C, de Beaucoudrey L, Emile JF, Arkwright PD, Schreiber RD, Rolinck-Werninghaus C, Rosen-Wolff A, Magdorf K, Roesler J, Casanova JL. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet. 2006 Aug 18;2(8):e131. PMID:16934001 doi:10.1371/journal.pgen.0020131
5. ↑ Tsumura M, Okada S, Sakai H, Yasunaga S, Ohtsubo M, Murata T, Obata H, Yasumi T, Kong XF, Abhyankar A, Heike T, Nakahata T, Nishikomori R, Al-Muhsen S, Boisson-Dupuis S, Casanova JL, Alzahrani M, Shehri MA, Elghazali G, Takihara Y, Kobayashi M. Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease. Hum Mutat. 2012 Sep;33(9):1377-87. doi: 10.1002/humu.22113. Epub 2012 Jun 7. PMID:22573496 doi:10.1002/humu.22113
6. ↑ Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, Toubiana J, Itan Y, Audry M, Nitschke P, Masson C, Toth B, Flatot J, Migaud M, Chrabieh M, Kochetkov T, Bolze A, Borghesi A, Toulon A, Hiller J, Eyerich S, Eyerich K, Gulacsy V, Chernyshova L, Chernyshov V, Bondarenko A, Grimaldo RM, Blancas-Galicia L, Beas IM, Roesler J, Magdorf K, Engelhard D, Thumerelle C, Burgel PR, Hoernes M, Drexel B, Seger R, Kusuma T, Jansson AF, Sawalle-Belohradsky J, Belohradsky B, Jouanguy E, Bustamante J, Bue M, Karin N, Wildbaum G, Bodemer C, Lortholary O, Fischer A, Blanche S, Al-Muhsen S, Reichenbach J, Kobayashi M, Rosales FE, Lozano CT, Kilic SS, Oleastro M, Etzioni A, Traidl-Hoffmann C, Renner ED, Abel L, Picard C, Marodi L, Boisson-Dupuis S, Puel A, Casanova JL. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011 Aug 1;208(8):1635-48. doi: 10.1084/jem.20110958. Epub 2011 Jul 4. PMID:21727188 doi:10.1084/jem.20110958
7. ↑ van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, Arts P, Rosentul DC, Carmichael AJ, Smits-van der Graaf CA, Kullberg BJ, van der Meer JW, Lilic D, Veltman JA, Netea MG. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011 Jul 7;365(1):54-61. doi: 10.1056/NEJMoa1100102. Epub 2011 Jun , 29. PMID:21714643 doi:10.1056/NEJMoa1100102
8. ↑ Hung HL, Lau J, Kim AY, Weiss MJ, Blobel GA. CREB-Binding protein acetylates hematopoietic transcription factor GATA-1 at functionally important sites. Mol Cell Biol. 1999 May;19(5):3496-505. PMID:10207073
9. ↑ Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, Montminy M, Evans RM. A transcriptional switch mediated by cofactor methylation. Science. 2001 Dec 21;294(5551):2507-11. Epub 2001 Nov 8. PMID:11701890 doi:10.1126/science.1065961
10. ↑ Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7. Epub 2004 Jun 25. PMID:15220471 doi:10.1073/pnas.0400593101
11. ↑ Kuo HY, Chang CC, Jeng JC, Hu HM, Lin DY, Maul GG, Kwok RP, Shih HM. SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):16973-8. Epub 2005 Nov 15. PMID:16287980 doi:10.1073/pnas.0504460102
12. ↑ Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K. Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10626-31. PMID:9724754
13. ↑ Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Janne OA, Palvimo JJ, Silvennoinen O. PIAS proteins promote SUMO-1 conjugation to STAT1. Blood. 2003 Nov 1;102(9):3311-3. Epub 2003 Jul 10. PMID:12855578 doi:10.1182/blood-2002-12-3816
14. ↑ Rogers RS, Horvath CM, Matunis MJ. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J Biol Chem. 2003 Aug 8;278(32):30091-7. Epub 2003 May 22. PMID:12764129 doi:10.1074/jbc.M301344200
15. ↑ DeVries TA, Kalkofen RL, Matassa AA, Reyland ME. Protein kinase Cdelta regulates apoptosis via activation of STAT1. J Biol Chem. 2004 Oct 29;279(44):45603-12. Epub 2004 Aug 20. PMID:15322115 doi:10.1074/jbc.M407448200
16. ↑ Krejci P, Salazar L, Kashiwada TA, Chlebova K, Salasova A, Thompson LM, Bryja V, Kozubik A, Wilcox WR. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008;3(12):e3961. doi: 10.1371/journal.pone.0003961. Epub 2008 Dec 17. PMID:19088846 doi:10.1371/journal.pone.0003961
17. ↑ Wojciak JM, Martinez-Yamout MA, Dyson HJ, Wright PE. Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains. EMBO J. 2009 Apr 8;28(7):948-58. Epub 2009 Feb 12. PMID:19214187 doi:10.1038/emboj.2009.30