UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors

Abstract

The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are more susceptible to lethal RNA virus infection than wild type littermates. Mechanistically, UBR5 mediates the Lysine 63-linked ubiquitination of Tripartite Motif Protein 28 (TRIM28), an epigenetic repressor of RLRs. This modification prevents intramolecular SUMOylation of TRIM28, thus disengages the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling

“…Our recent work has demonstrated EMCV replication was ~ 100-fold higher in the heart than that in other tissues on day 4 post infection (p.i.) 25 . Critically, Ubxn9 −/− mice were more susceptible to EMCV-induced lethality, accompanied by higher viral loads in the blood and heart relative to Ubxn9 +/+ mice ( Fig.…”

“…ONNV UgMP30 strain (NR-51661) was provided by BEI Resources. Green fluorescence protein (GFP)-VSV was made by inserting a VSV-G/GFP fusion sequence between the VSV G and L genes and propagated in our lab for use in several studies 25 , 74 , 76 . These viruses were propagated in Vero cells and titrated by a plaque forming assay.…”