Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis.
Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis.
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DOI：
10.1016/j.jaci.2013.01.052
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发表时间：
2013-06
影响因子：
14.2
通讯作者：
Holland, Steven M.
中科院分区：
文献类型：
--
作者：
Sampaio, Elizabeth P.;Hsu, Amy P.;Pechacek, Joseph;Bax, Hannelore I.;Dias, Dalton L.;Paulson, Michelle L.;Chandrasekaran, Prabha;Rosen, Lindsey B.;Carvalho, Daniel S.;Ding, Li;Vinh, Donald C.;Browne, Sarah K.;Datta, Shrimati;Milner, Joshua D.;Kuhns, Douglas B.;Priel, Debra A. Long;Sadat, Mohammed A.;Shiloh, Michael;De Marco, Brendan;Alvares, Michael;Gillman, Jason W.;Ramarathnam, Vivek;de la Morena, Maite;Bezrodnik, Liliana;Moreira, Ileana;Uzel, Gulbu;Johnson, Daniel;Spalding, Christine;Zerbe, Christa S.;Wiley, Henry;Greenberg, David E.;Hoover, Susan E.;Rosenzweig, Sergio D.;Galgiani, John N.;Holland, Steven M.
关键词：
干扰素-γ/IL-12途径的信号受损导致对分枝杆菌和二相性酵母的严重播散性感染的易感性。信号转导和转录激活因子1(STAT1)的显性功能增益突变与慢性皮肤黏膜念珠菌病有关。我们试图确定播散性二相性酵母感染患者的分子缺陷。对PBMC、EB病毒转化的B细胞和U3A细胞系进行了干扰素-γ/IL-12途径功能的研究。对先证者和现有亲属中的STAT1进行了测序。研究了干扰素诱导的STAT1磷酸化、转录反应、蛋白质-蛋白质相互作用、靶基因激活和功能。我们确定了5例播散性球虫免疫炎或组织胞浆体患者，其STAT1螺旋卷曲或DNA结合区存在杂合性错义突变。这些是显性的功能获得突变，导致STAT1磷酸化增强，延迟去磷酸化，DNA结合和反式激活增强，以及与激活的STAT1的蛋白抑制物相互作用增强。这些突变导致干扰素-γ诱导的基因表达增强，但我们发现对干扰素-γ重新刺激的反应减弱。STAT1的功能获得突变易于发生侵袭性的、严重的、播散性的二形性酵母感染，可能是通过对干扰素-γ介导的炎症的异常调节。
Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ–induced gene expression, but we found impaired responses to IFN-γ restimulation. Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ–mediated inflammation.
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影响因子：
3.7
作者：
Filipowicz M;Bernsmeier C;Terracciano L;Duong FH;Heim MH
通讯作者：
Heim MH
DOI：
10.3390/ijerph8041150
发表时间：
2011-04-01
影响因子：
--
作者：
Hector, Richard F.;Rutherford, George W.;Galgiani, John N.
通讯作者：
Galgiani, John N.
影响因子：
3.6
作者：
Averbuch, Diana;Chapgier, Ariane;Engelhard, Dan
通讯作者：
Engelhard, Dan
影响因子：
5.8
作者：
Haverkamp, MH;van Dissel, JT;Holland, SM
通讯作者：
Holland, SM
影响因子：
4.4
作者：
Chapgier, Ariane;Wynn, Robert F.;Arkwright, Peter D.
通讯作者：
Arkwright, Peter D.