{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:03:38Z","timestamp":1789625018323,"version":"build-2803163510"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>ISG15 is a type I interferon (IFN-I)-inducible ubiquitin-like protein that restrains IFN-I signaling. Classical ISG15 deficiency is thought to cause disease mainly by disrupting USP18 stabilization, which leads to sustained IFN-I signaling and interferon-driven autoinflammation. Whether patient-derived C-terminal ISG15 variants can impair IFN-I negative feedback through altered C-terminal functional presentation has remained unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We studied a Chinese boy with early-onset recurrent fever, severe ulcerative skin lesions, and elevated liver enzymes. Whole-exome sequencing was performed to identify ISG15 variants. Patient peripheral blood mononuclear cells (PBMCs) and skin tissue were analyzed for IFN-I pathway activation. Functional effects of the identified variants were assessed in 293T cells, and structural analysis was performed. The patient was treated with the JAK inhibitor baricitinib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Two novel compound heterozygous ISG15 variants were identified: c.234C&amp;gt;A, which produced a truncated ISG15 protein, and c.498A&amp;gt;T, a stop-loss variant predicted to extend the ISG15 C-terminus and associated with markedly impaired ISGylation. Patient PBMCs and skin tissue showed increased p-STAT1 signaling and IFN-I pathway activation, with decreased USP18 expression and altered ISG15-USP18 regulation in PBMCs. In 293T cells, c.498A&amp;gt;T alone did not reduce USP18 abundance, suggesting that this variant contributes to disease through impaired C-terminal functional presentation rather than USP18 loss alone. Structural analysis suggested that the C-terminal extension may alter LRLRGG motif presentation, weakening ISG15-USP18-mediated negative feedback. Baricitinib reduced IFN-I-related markers and was associated with improvement of ulcerative skin lesions and liver enzyme abnormalities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study expands the genetic and mechanistic spectrum of ISG15-associated type I interferonopathy, and supports that JAK-STAT inhibition with baricitinib can effectively control IFN-I-driven inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1916670","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:31:28Z","timestamp":1789623088000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel stop-loss variant in ISG15 causes C-terminal dysfunction and impairs USP18-mediated negative feedback"],"prefix":"10.3389","volume":"17","author":[{"given":"Wanyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongbin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingfeng","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health (NCCH)","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijiu","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlu","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyue","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huawei","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Children\u2019s Hospital of Capital Medical University, National Center for Children\u2019s Health of China","place":["Beijing, China"]},{"name":"Ministry of Education Key Laboratory of Major Diseases in Children","place":["Beijing, China"]},{"name":"Beijing Key Laboratory for Genetics of Birth Defects","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Precision Diagnosis and Treatment of Pediatric Immune Diseases","place":["Beijing, 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