RNF144A shapes the hierarchy of cytokine signaling to provide protective immunity against influenza
| Autor: | N. Merle, Dragana Jankovic, N. Cheru, Suman Mitra, Arian Laurence, Zu-Xi Yu, Hiroyuki Nagashima, Claudia Kemper, Alejandro V. Villarino, Majid Kazemian, Susan D. John, M. Bijlmakers, Estefania Nova-Lamperti, John J. O'Shea, Bingyu Yan, Erin E. West, Behdad Afzali, Gregory Weitsman, Daniel Chauss, S. Kim, Tilo Freiwald |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
biology Effector medicine.medical_treatment 3. Good health Cell biology Ubiquitin ligase 03 medical and health sciences 0302 clinical medicine Cytokine Immune system Granzyme biology.protein medicine Tumor necrosis factor alpha Signal transduction 030217 neurology & neurosurgery STAT5 030304 developmental biology |
| DOI: | 10.1101/782680 |
| Popis: | Cytokine-induced signaling pathways are tightly regulated and self-limiting, as their dysregulation causes immune disorders and cancer. The precise mechanisms that fine-tune these responses are incompletely understood. We show that the E3 ubiquitin ligaseRNF144Ais an IL-2/STAT5-induced gene in T cells and critically orchestrates the hierarchy of IL-2R signaling to promote STAT5 activation and limit RAF-ERK-MAPK output from the IL-2R. Mechanistically, RNF144A increased the interaction between IL-2Rβ and STAT5 and polyubiquitinated RAF1, enhancing its proteasomal degradation and preventing the formation of the potent RAF1/BRAF kinase complex. CD8+T cells fromRnf144a–/–mice had impaired IL-2-induction of effector genes, includingTnfand granzymes, and these mice demonstrated increased susceptibility to influenza. Reduced RNF144A expression was associated with more severe influenza in humans and its expression in patients was a biomarker distinguishing moderate from severe disease. These studies reveal a vital physiological role for RNF144A in maintaining the fidelity of IL-2R signaling in CTLs to prevent severe inflammation in response to infection.One Sentence SummaryRNF144A promotes anti-viral immunity by regulating the hierarchy of cytokine signal output |
| Databáze: | OpenAIRE |
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