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Dysregulation of the IL-3\/STAT5 signaling have been associated with inflammatory and autoimmune diseases characterized by inflammatory cell infiltration and organ damage. IL-3 receptor \u03b1 (IL-3R\u03b1) specifically binds to IL-3 and initiates intracellular signaling, resulting in the phosphorylation of STAT5. However, the regulatory mechanisms of IL-3R\u03b1 remain unclear. Here, we identified the E3 ubiquitin ligase RNF128 as a negative regulator of IL-3\/STAT5 signaling by targeting IL-3R\u03b1 for lysosomal degradation. RNF128 was shown to selectively bind to IL-3R\u03b1, without interacting with the common beta chain IL-3R\u03b2, which shares the subunit with GM-CSF. The deficiency of <jats:italic>Rnf128<\/jats:italic> had no effect on GM-CSF-induced phosphorylation of Stat5, but it resulted in heightened Il-3-triggered activation of Stat5 and increased transcription of the <jats:italic>Id1<\/jats:italic>, <jats:italic>Pim1<\/jats:italic>, and <jats:italic>Cd69<\/jats:italic> genes. Furthermore, we found that RNF128 promoted the K27-linked polyubiquitination of IL-3R\u03b1 in a ligase activity-dependent manner, ultimately facilitating its degradation through the lysosomal pathway. RNF128 inhibited the activation and chemotaxis of macrophages in response to LPS stimulation, thereby attenuating excessive inflammatory responses. Collectively, these results reveal that RNF128 negatively regulates the IL-3\/STAT5 signaling pathway by facilitating K27-linked polyubiquitination of IL-3R\u03b1. This study uncovers E3 ubiquitin ligase RNF128 as a novel regulator of the IL-3\/STAT5 signaling pathway, providing potential molecular targets for the treatment of inflammatory diseases.<\/jats:p>","DOI":"10.1186\/s12964-024-01636-4","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T09:02:43Z","timestamp":1714726963000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["E3 ubiquitin ligase RNF128 negatively regulates the IL-3\/STAT5 signaling pathway by facilitating K27-linked polyubiquitination of IL-3R\u03b1"],"prefix":"10.1186","volume":"22","author":[{"given":"Jingge","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianguo","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ao","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian-Sheng","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"key":"1636_CR1","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1126\/science.aaa4268","volume":"347","author":"GF Weber","year":"2015","unstructured":"Weber GF, Chousterman BG, He S, Fenn AM, Nairz M, Anzai A, Brenner T, Uhle F, Iwamoto Y, Robbins CS, et al. 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All animal experiments were conducted in accordance with the guidelines established by the International Committees for the Care and Use of Laboratory Animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"254"}}