RT Journal Article
SR Electronic
T1 RNF144A shapes the hierarchy of cytokine signaling to provide protective immunity against influenza
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 782680
DO 10.1101/782680
A1 B. Afzali
A1 S. Kim
A1 E. West
A1 E. Nova-Lamperti
A1 N. Cheru
A1 H. Nagashima
A1 B. Yan
A1 T Freiwald
A1 N. Merle
A1 D. Chauss
A1 M. Bijlmakers
A1 G. Weitsman
A1 Z. Yu
A1 D. Jankovic
A1 S. Mitra
A1 A. Villarino
A1 C. Kemper
A1 A. Laurence
A1 M. Kazemian
A1 J.J. O’Shea
A1 S. John
YR 2019
UL http://biorxiv.org/content/early/2019/09/26/782680.abstract
AB 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-2Rβ 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.One Sentence Summary RNF144A promotes anti-viral immunity by regulating the hierarchy of cytokine signal output