A partial form of inherited human USP18 deficiency underlies infection and inflammation.
A partial form of inherited human USP18 deficiency underlies infection and inflammation.
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DOI：
10.1084/jem.20211273
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发表时间：
2022-04-04
期刊：
影响因子：
--
通讯作者：
Bogunovic D
中科院分区：
文献类型：
--
作者：
Martin-Fernandez M;Buta S;Le Voyer T;Li Z;Dynesen LT;Vuillier F;Franklin L;Ailal F;Muglia Amancio A;Malle L;Gruber C;Benhsaien I;Altman J;Taft J;Deswarte C;Roynard M;Nieto-Patlan A;Moriya K;Rosain J;Boddaert N;Bousfiha A;Crow YJ;Jankovic D;Sher A;Casanova JL;Pellegrini S;Bustamante J;Bogunovic D
Martin-Fernandez等人。描述部分USP18缺乏的患者，这是I型干扰素病和孟德尔人对分枝杆菌病(MSMD)易感性的基础。这项工作描述了缺乏干扰素-I信号通路的负调控导致干扰素-γ-白介素12环路的抑制是MSMD的一个原因。人USP18是干扰素刺激的基因产物，是I型干扰素信号的负调控因子。它还从蛋白质中去除共价连接的ISG15，这一过程被称为去ISG化。反过来，ISG15防止USP18被蛋白酶体降解。常染色体隐性遗传性完全性USP18缺乏症在婴儿期由于不受控制的干扰素-I介导的自体炎症而危及生命。我们报告了三个患有自体炎症和分枝杆菌疾病的摩洛哥兄弟姐妹，他们是一种新的USP18变种的纯合子。我们证明突变的USP18(p.I60N)通常被ISG15稳定并有效地去ISG，但与受体锚定的STAT2相互作用很差，并且在干扰素-I信号的负调控中受损。我们还表明，由于干扰素-I介导的髓系细胞产生IL-12和IL-23的损伤，干扰素-γ依赖的IL-12和IL-23的诱导减少。因此，USP18-I60N对干扰素-I信号的负调控不足是一种特殊的I型干扰素病的基础，它损害了髓系细胞产生IL-12和IL-23，从而解释了分枝杆菌病的易感性。
Martin-Fernandez et al. describe patients with partial USP18 deficiency, which underlies both type I interferonopathy and Mendelian susceptibility to mycobacterial disease (MSMD). This work delineates the lack of negative regulation of the IFN-I signaling pathway leading to depression of the IFN-γ–IL12 loop as a cause of MSMD. Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I–mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ–dependent induction of IL-12 and IL-23 is reduced owing to IFN-I–mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease.
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DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
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通讯作者：
Goldbach-Mansky R
影响因子：
39.3
作者：
Liu T;Zhang L;Joo D;Sun SC
通讯作者：
Sun SC
DOI：
10.1084/jem.20151529
发表时间：
2016-06-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Meuwissen ME;Schot R;Buta S;Oudesluijs G;Tinschert S;Speer SD;Li Z;van Unen L;Heijsman D;Goldmann T;Lequin MH;Kros JM;Stam W;Hermann M;Willemsen R;Brouwer RW;Van IJcken WF;Martin-Fernandez M;de Coo I;Dudink J;de Vries FA;Bertoli Avella A;Prinz M;Crow YJ;Verheijen FW;Pellegrini S;Bogunovic D;Mancini GM
通讯作者：
Mancini GM
DOI：
10.1126/science.aaa4282
发表时间：
2015-08-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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通讯作者：
Casanova JL
影响因子：
4.1
作者：
Francois-Newton, Veronique;Livingstone, Mark;Pellegrini, Sandra
通讯作者：
Pellegrini, Sandra