Abstract
Post-translational modifications, including O-GlcNAcylation, play fundamental roles in modulating cellular events, including transcription, signal transduction, and immune signaling. Several molecular targets of O-GlcNAcylation associated with pathogen-induced innate immune responses have been identified; however, the direct regulatory mechanisms linking O-GlcNAcylation with antiviral RIG-I-like receptor signaling are not fully understood. In this study, we found that cellular levels of O-GlcNAcylation decline in response to infection with Sendai virus. We identified a heavily O-GlcNAcylated serine-rich region between amino acids 249–257 of the mitochondrial antiviral signaling protein (MAVS); modification at this site disrupts MAVS aggregation and prevents MAVS-mediated activation and signaling. O-GlcNAcylation of the serine-rich region of MAVS also suppresses its interaction with TRAF3; this prevents IRF3 activation and production of interferon-β. Taken together, these results suggest that O-GlcNAcylation of MAVS may be a master regulatory event that promotes host defense against RNA viruses.
Highlights
Innate immune signaling in vertebrate species is orchestrated by three types of receptor families; toll-like-receptors (TLRs), NOD-like receptors, and RIG-I-like receptors (RLRs)
We confirmed that SeV infection resulted in elevated levels of intracellular O-GlcNAcylation in monocytemacrophage U937 cells in response to differentiation with phorbol 12-myristate 13-acetate; these findings are consistent with those reported previously in which infection of macrophages with an RNA virus resulted in a substantial increase in intracellular O-GlcNAcylation (Figure 1A) [9, 10]
Attempts have been made to identify a role for glucose metabolism, the central pathway associated with energy metabolism, in modulating one or more aspects of the innate immune response
Summary
Innate immune signaling in vertebrate species is orchestrated by three types of receptor families; toll-like-receptors (TLRs), NOD-like receptors, and RIG-I-like receptors (RLRs). O-GlcNAcylation of MAVS Inhibits Its Activity viral dsRNA, RIG-I undergoes various post-translational modifications, including acetylation and ubiquitination [1,2,3]. Interferon (IFN) regulatory factor-3 (IRF3) and NF-kB are phosphorylated sequentially and translocated to the nucleus; these transcription factors (TFs) promote the production of type I IFNs, pro-inflammatory cytokines, and antiviral factors that are secreted and can modulate the responses of neighboring cells [5]. This process contributes to host defense by promoting virus clearance
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