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JAK抑制剂治疗一例遗传性USP18缺乏症患儿
JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency


Fahad Alsohime ... 其他 • 2020.01.16

摘要


泛素特异性肽酶18(USP18)缺乏症是一种重型Ⅰ型干扰素病。USP18可阻断Janus相关激酶1(JAK1)与Ⅰ型干扰素受体之间的相互作用,从而下调Ⅰ型干扰素信号传导。USP18缺乏所导致的干扰素介导的炎症无法缓解,并且在围生期具有致死性。本文介绍了一个新生儿病例,该病例患有脑积水、坏死性蜂窝织炎、全身炎症和呼吸衰竭。外显子组测序发现USP18上的一个重要剪接位点有一个纯合突变。编码的蛋白可表达,但不具有负调节功能。经鲁索替尼(ruxolitinib)治疗后,患儿迅速且持续好转(由沙特国王大学[King Saud University]等资助)。

Ⅰ型干扰素病是一种单基因自身炎性疾病1-3,其特征是Ⅰ型干扰素生成过多或对Ⅰ型干扰素的应答增强1-4。USP18可阻断JAK1和Ⅰ型干扰素受体复合物中Ⅰ型干扰素受体2(IFNAR2)亚基之间的相互作用,从而下调Ⅰ型干扰素的信号传导5-7(图1)。USP18还具有酶活性,可将由干扰素刺激基因15(ISG15)编码并且共价结合的15kDa蛋白从其靶点上移除,这一过程称作去ISG化8。最后,在不依赖其对于ISG化蛋白的亲和力的情况下,USP18还可结合游离ISG15,而ISG15可保护USP18免受蛋白酶体降解,从而增强其负调节能力9

 

图1. USP18的分子功能

Ⅰ型干扰素(IFN-Ⅰ)与IFN-Ⅰ受体结合,IFN-Ⅰ受体包括两个亚基,IFN-Ⅰ受体1(IFNAR1)和IFN-Ⅰ受体2(IFNAR2)。它通过激活两个受体相关蛋白酪氨酸激酶(Janus激酶1[JAK1]和酪氨酸激酶2[TYK2])的方式发出信号,这些激酶将信号转导及转录激活因子1(STAT1)和2(STAT2)磷酸化(P),从而诱导数百个干扰素刺激基因(ISG)的转录。图A显示,USP18(一种ISG)抑制JAK1向IFNAR2的募集,从而作为IFN-Ⅰ信号传导的负反馈调节因子发挥活性。ISG15稳定USP18并保护其免受蛋白酶体降解,从而实现正常的ISG表达。图B显示,导致USP18无法合成的纯合突变造成IFN-Ⅰ信号不受限制,具有致死性。图C和图D显示,鲁索替尼(一种JAK1抑制剂)治疗之前和之后,病例报告中患者的结局。图中间的方框显示,除抑制JAK1之外,USP18还具有催化活性:它将泛素样ISG15蛋白从结合蛋白上裂解下来,这一过程被称为去ISG化。PICU表示儿科重症监护病房。





作者信息

Fahad Alsohime, M.D., Marta Martin-Fernandez, Ph.D., Mohamad-Hani Temsah, M.D., Majed Alabdulhafid, M.D., Tom Le Voyer, M.S., Malak Alghamdi, M.D., Xueer Qiu, M.S., Najla Alotaibi, M.D., Areej Alkahtani, M.D., Sofija Buta, M.S., Emmanuelle Jouanguy, Ph.D., Ayman Al-Eyadhy, M.D., Conor Gruber, B.S., Gamal M. Hasan, M.D., Fahad A. Bashiri, M.D., Rabih Halwani, Ph.D., Hamdy H. Hassan, M.D., Saleh Al-Muhsen, M.D., Nouf Alkhamis, M.D., Zobaida Alsum, M.D., Jean-Laurent Casanova, M.D., Ph.D., Jacinta Bustamante, M.D., Ph.D., Dusan Bogunovic, Ph.D., and Abdullah A. Alangari, M.D.
From the Department of Pediatrics (F.A., M.-H.T., M. Alabdulhafid, M. Alghamdi, N. Alotaibi, A.A., A.A.-E., G.M.H., F.A.B., S.A.-M., N. Alkhamis, Z.A., A.A.A.) and the Immunology Research Laboratory, Department of Pediatrics (R.H., S.A.-M.), College of Medicine, King Saud University, the Department of Pediatrics, College of Medicine, Imam Mohammed bin Saud University (A.A.), and the Department of Radiology and Medical Imaging, King Saud University Medical City (H.H.H.) — all in Riyadh, Saudi Arabia; the Departments of Microbiology and Pediatrics and the Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai (M.M.-F., X.Q., S.B., C.G., D.B.), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, the Rockefeller University (E.J., J.-L.C., J.B.), and Howard Hughes Medical Institute (J.-L.C.) — all in New York; Paris Descartes University, Imagine Institute, and the Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM Unité 1163 (T.L.V., E.J., J.-L.C., J.B.), and the Pediatric Hematology and Immunology Unit (J.-L.C.) and the Center for the Study of Primary Immunodeficiencies (J.B.), Assistance Publique–Hôpitaux de Paris, Necker Hospital for Sick Children — all in Paris; the Department of Pediatrics, Assiut Faculty of Medicine, Assiut University, Assiut, Egypt (G.M.H.); and Sharjah Institute for Medical Research, Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates (R.H.). Address reprint requests to Dr. Alangari at the Department of Pediatrics, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia, or at aangari@ksu.edu.sa; or to Dr. Bogunovic at the Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., New York, NY 10021, or at dusan.bogunovic@mssm.edu.

 

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