期刊
JOURNAL OF CLINICAL IMMUNOLOGY
卷 32, 期 4, 页码 681-689出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-012-9659-2
关键词
STAT1; SH2 domain; mycobacterial disease; IFN-gamma
类别
资金
- Division of Intramural Research of National Institute of Allergy and Infectious Diseases, National Institutes of Health
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
STAT1 is a key component of Interferon (IFN)-gamma and IFN-alpha signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-gamma driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T > A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-gamma driven GAS-luciferase activity, and expression of IFN-gamma target genes are reduced. IFN-alpha driven ISRE response, but not IFN-alpha driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-gamma related immunity and is recessive for IFN-alpha induced immune function.
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