Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation.
Interferons (IFN) alpha/beta and gamma induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss of GAF and ISGF3 activation but is dominant for one cellular phenotype and recessive for the other. It impairs the nuclear accumulation of GAF but not of ISGF3 in heterozygous cells stimulated by IFNs. Thus, the antimycobacterial, but not the antiviral, effects of human IFNs are principally mediated by GAF.
Dupuis
S
S
Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-INSERM UMR550, Faculté de Médecine Necker-Enfants Malades, 75015 Paris, France.
Dargemont
C
C
Fieschi
C
C
Thomassin
N
N
Rosenzweig
S
S
Harris
J
J
Holland
S M
SM
Schreiber
R D
RD
Casanova
J L
JL
D000328:Adult; D000818:Animals; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D018095:Germ-Line Mutation; D006801:Humans; D007109:Immunity / Q000235:genetics; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D053613:Janus Kinase 1; D051379:Mice; D009164:Mycobacterium Infections / Q000235:genetics / Q000276:immunology*; D015269:Mycobacterium avium Complex / Q000276:immunology; D015270:Mycobacterium avium-intracellulare Infection / Q000235:genetics / Q000276:immunology; D009163:Mycobacterium bovis; D010375:Pedigree; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013539:Simian virus 40; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology*
D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; C494228:Isgf3g protein, mouse; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1