Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-γ-dependent innate immunity

被引:213
作者
Varinou, L
Ramsauer, K
Karaghiosoff, M
Kolbe, T
Pfeffer, K
Müller, M
Decker, T
机构
[1] Univ Vienna, Max F Perutz Labs, Univ Dept Vienna Bioctr, Dept Genet & Microbiol, A-1030 Vienna, Austria
[2] Vet Univ Vienna, Inst Genet & Anim Breeding, A-1210 Vienna, Austria
[3] Inst Agrobiotechnol Tulln, Dept Biotechnol Anim Prod, A-3430 Tulln, Austria
[4] Univ Dusseldorf, Inst Med Microbiol, D-40225 Dusseldorf, Germany
基金
奥地利科学基金会;
关键词
D O I
10.1016/S1074-7613(03)00322-4
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Stat1 is phosphorylated on serine 727 within its transactivating domain (TAD) in response to interferons or other immunological signals. We generated gene-targeted mutant mice expressing a serine727-alanine mutant of Stat1. These animals showed increased mortality upon infection with Listeria monocytogenes and impaired clearance of the bacteria from spleen and liver. The Stat1S727A mice were more resistant to the LPS-induced septic shock syndrome, suggesting that Stat1 serine phosphorylation promotes inflammatory responses. Expression of IFN-gamma-induced genes was strongly reduced in macrophages expressing Stat1(S727A). While mutation of Stat1 at S727 did not reduce its binding to chromatin, association with the coactivator CBP and histone acetylation at the interferon-responsive GBP promoter was strongly reduced, suggesting defective recruitment of histone acetylases as the mechanism underlying IFN-gamma hyporesponsiveness. Our data demonstrate that the increase in transcription factor activity caused by Stat1 serine phosphorylation contributes to macrophage activation and to IFN-gamma-dependent immune responses in vivo.
引用
收藏
页码:793 / 802
页数:10
相关论文
共 39 条
[1]   Stat1-dependent, p53-independent expression of p21waf1 modulates oxysterol-induced apoptosis [J].
Agrawal, S ;
Agarwal, ML ;
Chatterjee-Kishore, M ;
Stark, GR ;
Chisolm, GM .
MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (07) :1981-1992
[2]   Genomic organization and chromosomal localization of a new member of the murine interferon-induced guanylate-binding protein family [J].
Anderson, SL ;
Carton, JM ;
Zhang, X ;
Rubin, BY .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 1999, 19 (05) :487-494
[3]  
BACCARINI M, 1985, J IMMUNOL, V134, P2658
[4]   COMBINATORIAL ASSOCIATION AND ABUNDANCE OF COMPONENTS OF INTERFERON-STIMULATED GENE FACTOR-3 DICTATE THE SELECTIVITY OF INTERFERON RESPONSES [J].
BLUYSSEN, HAR ;
MUZAFFAR, R ;
VLIESTSTRA, RJ ;
VANDERMADE, ACJ ;
LEUNG, S ;
STARK, GR ;
KERR, IM ;
TRAPMAN, J ;
LEVY, DE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (12) :5645-5649
[5]  
BRIKEN V, 1995, MOL CELL BIOL, V15, P975
[6]   INTERFERON-GAMMA RECEPTOR-DEFICIENT MICE ARE RESISTANT TO ENDOTOXIC-SHOCK [J].
CAR, BD ;
ENG, VM ;
SCHNYDER, B ;
OZMEN, L ;
HUANG, S ;
GALLAY, P ;
HEUMANN, D ;
AGUET, M ;
RYFFEL, B .
JOURNAL OF EXPERIMENTAL MEDICINE, 1994, 179 (05) :1437-1444
[7]   Inactivation of LRG-47 and IRG-47 reveals a family of interferon γ-inducible genes with essential, pathogen-specific roles in resistance to infection [J].
Collazo, CM ;
Yap, GS ;
Sempowski, GD ;
Lusby, KC ;
Tessarollo, L ;
Woude, GFV ;
Sher, A ;
Taylor, GA .
JOURNAL OF EXPERIMENTAL MEDICINE, 2001, 194 (02) :181-187
[8]   Activation of protein kinase Cδ by IFN-γ [J].
Deb, DK ;
Sassano, A ;
Lekmine, F ;
Majchrzak, B ;
Verma, A ;
Kambhampati, S ;
Uddin, S ;
Rahman, A ;
Fish, EN ;
Platanias, LC .
JOURNAL OF IMMUNOLOGY, 2003, 171 (01) :267-273
[9]   Serine phosphorylation of STATs [J].
Decker, T ;
Kovarik, P .
ONCOGENE, 2000, 19 (21) :2628-2637
[10]   Targeted disruption of the mouse STAT1 results in compromised innate immunity to viral disease [J].
Durbin, JE ;
Hackenmiller, R ;
Simon, MC ;
Levy, DE .
CELL, 1996, 84 (03) :443-450