ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1646996
This article is part of the Research TopicAutoinflammatory novelties: from pathogenic mechanisms to clinical and therapeutic implicationsView all 11 articles
Novel USP18 mutations lead to severe interferonopathy responsive to JAK inhibitor
Provisionally accepted
- 1Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- 2Department of Rheumatology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China
- 3Department of Rheumatology and Immunology, Beijing Children's Hospital Capital Medical University, Beijing, China
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Ubiquitin-specific peptidase 18 (USP18) is an interferon (IFN) α/β-induced protein and a key negative regulator of interferon response. USP18 deficiency causes embryonic or neonatal lethality with severe systemic inflammation and neurological anomalies due to excessive IFN signatures. In this study, we described novel loss-of-function biallelic mutations of USP18 in two patients from a family with severe early-onset systemic inflammation. Patient PBMCs exhibited hypersensitivity to IFNα, leading to aberrant and prolonged activation of type I IFN signaling. In addition, our study revealed a novel pathogenic mechanism of the USP18 missense mutation (p.G317S), which weakened its negative regulatory function by impairing its interaction with ISG15. Consequently, the combination of a nonsense mutation (p.C230X) and a missense mutation caused USP18 deficiency, thereby failing to attenuate type I IFN signaling. Treatment with JAK inhibitor ruxolitinib alleviated the inflammatory phenotypes, followed by a sustained recovery.
Keywords: USP18, Type I interferonopathies, Autoinflammation, type I interferon, targeted therapy
Received: 14 Jun 2025; Accepted: 19 Aug 2025.
Copyright: © 2025 Sun, Li, Dou, Wang, Lai, Zhu, Zhou and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jia Zhu, Department of Rheumatology and Immunology, Beijing Children's Hospital Capital Medical University, Beijing, China
Qing Zhou, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
Xiaomin Yu, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
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