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The expression level of MeCP2 is crucial, as indicated by the observation that loss\u2010of\u2010function mutations of <jats:italic>MECP2<\/jats:italic> cause Rett syndrome, whereas an extra copy spanning the <jats:italic>MECP2<\/jats:italic> locus results in <jats:italic>MECP2<\/jats:italic> duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia\u2013reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin\u20106 (IL\u20106)\/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48\u2010linked ubiquitination from MeCP2 prevented its proteasome\u2010dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin\u2010specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia\u2010induced MeCP2 degradation by cleaving lysine 48\u2010linked ubiquitin chains from MeCP2, primarily targeting its C\u2010terminal domain. Consistently, USP15 inhibited hypoxia\u2010induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL\u20106 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL\u20106 signaling.<\/jats:p>","DOI":"10.1111\/febs.17282","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T05:23:53Z","timestamp":1728365033000},"page":"153-167","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>USP15<\/scp> inhibits hypoxia\u2010induced <scp>IL<\/scp>\u20106 signaling by deubiquitinating and stabilizing <scp>MeCP2<\/scp>"],"prefix":"10.1111","volume":"292","author":[{"given":"Zi\u2010Tong","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology  Wuhan 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Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u2010Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zheng","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences Wuhan University  Wuhan 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