microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP

Xu Zhang, Clément Chapat, Peng Wang, Jung-Hyun Choi, Qian Li, Jun Luo, Shane Wiebe, Sung-Hoon Kim, Nathaniel Robichaud, Isabela Fabri Karam, David Dai, Angela P Hackett, Rongtuan Lin, Tommy Alain, Long Yang, Seyed Mehdi Jafarnejad, Nahum Sonenberg

Research output: Contribution to journalArticlepeer-review

Abstract

Type I interferons (IFNs) are critical cytokines in the host defense against invading pathogens. Sustained production of IFNs, however, is detrimental to the host, as it provokes autoimmune diseases. Thus, the expression of IFNs is tightly controlled. We report that the mRNA 5' cap-binding protein 4EHP plays a key role in regulating type I IFN concomitant with controlling virus replication, both in vitro and in vivo. Mechanistically, 4EHP suppresses IFN-β production by effecting the miR-34a-induced translational silencing of Ifnb1 mRNA. miR-34a is upregulated by both RNA virus infection and IFN-β induction, prompting a negative feedback regulatory mechanism that represses IFN-β expression via 4EHP. These findings demonstrate the direct involvement of 4EHP in virus-induced host response, underscoring a critical translational silencing mechanism mediated by 4EHP and miR-34a to impede sustained IFN production. This study highlights an intrinsic regulatory function for miRNA and the translation machinery in maintaining host homeostasis.

Original languageEnglish
JournalMolecular Cell
Early online date12 Feb 2021
DOIs
Publication statusEarly online date - 12 Feb 2021

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