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RNF144A shapes the hierarchy of cytokine signaling to provide protective immunity against influenza

Research output: Working paper/PreprintPreprint

B. Afzali, S. Kim, E. West, E. Nova-Lamperti, N. Cheru, H. Nagashima, B. Yan, T. Freiwald, N. Merle, D. Chauss, M. Bijlmakers, G. Weitsman, Z. Yu, D. Jankovic, S. Mitra, A. Villarino, C. Kemper, A. Laurence, M. Kazemian, J.J. O'Shea & 1 more S. John

Original languageEnglish
PublisherbioRxiv
Pages1-33
DOIs
E-pub ahead of print26 Sep 2019
Published26 Sep 2019

King's Authors

Abstract

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 ligase RNF144A is 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-2Rb and STAT5 and polyubiquitinated RAF1, enhancing its proteasomal degradation and preventing the formation of the potent RAF1/BRAF kinase complex. CD8+ T cells from Rnf144a-/- mice had impaired IL-2-induction of effector genes, including Tnf and 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.

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