Ubiquitination in the antiviral immune response

Abstract

Ubiquitination has long been known to regulate fundamental cellular processes through the induction of proteasomal degradation of target proteins. More recently, ‘atypical’ nondegradative types of polyubiquitin chains have been appreciated as important regulatory moieties by modulating the activity or subcellular localization of key signaling proteins. Intriguingly, many of these non-degradative types of ubiquitination regulate the innate sensing pathways initiated by pattern recognition receptors (PRRs), ultimately coordinating an effective antiviral immune response. Here we discuss recent advances in understanding the functional roles of degradative and atypical types of ubiquitination in innate immunity to viral infections, with a specific focus on the signaling pathways triggered by RIG-I-like receptors, Toll-like receptors, and the intracellular viral DNA sensor cGAS.

Long noncoding RNAs in viral infections

“…Among the regulators of the IFN pathway, factors involved in protein ubiquitination seem to have special relevance (reviewed in Davis and Gack, 2015). Ubiquitin is a polypeptide that can be covalently bound to a protein substrate (reviewed in Clague et al, 2015).…”

“…RIG-I can be ubiquitinated and degraded by RNF125 (Ring Finger Protein 125) and deubiquitinated and stabilized by USP4 (Wang et al, 2013; Luo et al, 2013). Further, RIG-I can be ubiquitinated and activated by TRIM25, which, in turn, can be ubiquitinated and degraded by LUBAC (linear ubiquitin chain assembly complex) and deubiquitinated and stabilized by USP15 (Davis and Gack, 2015) (Fig. 1).…”

Biochemistry and Molecular Biology of Flaviviruses

“…Proteins can be polyubiquitinated since ubiquitin itself can serve as a substrate; polyubiquitination is frequently recognized as a signal for protein degradation mediated by the proteasome complex. 374 As ubiquitination has been broadly implicated in multiple cellular processes, including regulation of innate immunity, 375 it is not surprising that viruses have evolved mechanisms to interface with the ubiquitin system.…”

Delicate coordination of TRIM21’s dual activity in virus neutralization and signaling

“…Ubiquitin is a small protein of 76 amino acids that is usually attached to lysine residues of proteins by a cascade of enzymes. Ubiquitin molecules are first activated by E1 enzymes, then conjugated by E2 enzymes, and are finally ligated to the substrate by E3 ligases (6). Ubiquitination may result in monoubiquitinated or polyubiquitinated proteins.…”

“…K48-linked polyubiquitin chains are well known to be recognized by the proteasome, triggering the degradation of the modified substrate. In contrast, K63-linked ubiquitin chains-both the covalently attached and unanchored forms-are generally believed to not trigger the proteasomal degradation of the substrate protein, but rather have important roles in activating signal transduction pathways (6). Mechanistically, K63-linked polyubiquitin can activate signaling pathways by either stabilizing the substrate protein or inducing its multimeric active form, or by facilitating the recruitment of other signaling proteins.…”