Signaling from the RNA sensor RIG-I is regulated by ufmylation.

Abstract

The RNA-binding protein RIG-I is a key initiator of the antiviral innate immune response. The signaling that mediates the antiviral response downstream of RIG-I is transduced through the adaptor protein MAVS and results in the induction of type I and III interferons (IFNs). This signal transduction occurs at endoplasmic reticulum (ER)–mitochondrial contact sites, to which RIG-I and other signaling proteins are recruited following their activation. RIG-I signaling is highly regulated to prevent aberrant activation of this pathway and dysregulated induction of IFN. Previously, we identified UFL1, the E3 ligase of the ubiquitin-like modifier conjugation system called ufmylation, as one of the proteins recruited to membranes at ER–mitochondrial contact sites in response to RIG-I activation. Here, we show that UFL1, as well as the process of ufmylation, promote IFN induction in response to RIG-I activation. We found that following RNA virus infection, UFL1 is recruited to the membrane-targeting protein 14–3-3ε and that this complex is then recruited to activated RIG-I to promote downstream innate immune signaling. Importantly, we found that 14–3-3ε has an increase in UFM1 conjugation following RIG-I activation. Additionally, loss of cellular ufmylation prevents the interaction of 14–3-3ε with RIG-I, which abrogates the interaction of RIG-I with MAVS and thus the downstream signal transduction that induces IFN. Our results define ufmylation as an integral regulatory component of the RIG-I signaling pathway and as a posttranslational control for IFN induction.

• Authors: Daltry L Snider, Moonhee Park, Kristen A Murphy, Dia C Beachboard, Stacy M Horner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 15 Pg. e2119531119 (04 12 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 35394863 (Publication Type: Journal Article)

Chemical References

• 14-3-3 Proteins
• RNA, Viral
• Receptors, Immunologic
• YWHAE protein, human
• Interferons
• Ubiquitin-Protein Ligases
• DDX58 protein, human
• DEAD Box Protein 58
• UFL1 protein, human

Topics

• 14-3-3 Proteins (metabolism)
• DEAD Box Protein 58 (metabolism)
• Humans
• Immunity, Innate
• Interferons (metabolism)
• RNA Virus Infections (genetics, immunology)
• RNA, Viral (metabolism)
• Receptors, Immunologic (metabolism)
• Signal Transduction
• Ubiquitin-Protein Ligases (metabolism)