Viperin: An ancient radical SAM enzyme finds its place in modern cellular metabolism and innate immunity

Abstract

Viperin plays an important and multifaceted role in the innate immune response to viral infection. Viperin is also notable as one of very few radical SAM-dependent enzymes present in higher animals; however, the enzyme appears broadly conserved across all kingdoms of life, which suggests that it represents an ancient defense mechanism against viral infections. Although viperin was discovered some 20 years ago, only recently was the enzyme’s structure determined and its catalytic activity elucidated. The enzyme converts CTP to 3’,4’-didehydro-3’-deoxy-CTP, which functions as novel chain-terminating antiviral nucleotide when misincorporated by viral RNA-dependent RNA polymerases. Moreover, in higher animals, viperin interacts with numerous other host and viral proteins, and it is apparent that this complex network of interactions constitutes another important aspect of the protein’s antiviral activity. An emerging theme is that viperin appears to facilitate ubiquitin-dependent proteasomal degradation of some of the proteins it interacts with. Viperin- targeted protein degradation contributes to the antiviral response either by down-regulating various metabolic pathways important for viral replication or by directly targeting viral proteins for degradation. Here, we review recent advances in our understanding of the structure and catalytic activity of viperin, together with studies investigating the interactions between viperin and its target proteins. These studies have provided detailed insights into the biochemical processes underpinning this unusual enzyme’s wide-ranging antiviral activity. We also highlight recent intriguing reports that implicate a broader role for viperin in regulating non-pathological cellular processes, including thermogenesis and protein secretion.

Viperin inhibits cholesterol biosynthesis and interacts with enzymes in the cholesterol biosynthetic pathway

“…Although this is not a large change in protein levels, it does suggest that viperin may reduce SM levels by increasing its rate of proteasomal degradation. In support of this idea, the ubiquitin-dependent degradation of SM is known to be regulated in response to cellular cholesterol levels through the action of the E3 ubiquitin ligase MARCH6 (11) and it is generally considered that viperin exerts some of its antiviral effects by increasing the rate of proteasomal degradation of its target proteins (15, 68). Although the evidence for viperin’s interaction with proteasomal degradation machinery is indirect, viperin is known to activate TRAF6, which is an E3 ligase involved in the K63-linked polyubiquitination of proteins involved in immune signaling (49, 51).…”

Viperin interacts with PEX19 to mediate peroxisomal augmentation of the innate antiviral response

“…Pex19 is essential for the function and early biogenesis of peroxisomes, and acts as a chaperone to shuttle peroxisomal proteins from the ER to the peroxisome ( Gotte et al, 1998 ; Matsuzono et al, 1999 ). Although the significance of viperin binding to Pex19 is not immediately apparent, it is becoming increasingly evident that peroxisomes are emerging as critical organelles in antiviral defense, specifically through activation of MAVS that is present on the outer peroxisomal membrane and downstream induction of both type I and III IFNs ( Dixit et al, 2010 ; Bender et al, 2015 ; Ghosh & Marsh, 2020 ). Further evidence that peroxisomes play a role in antiviral defenses comes from the growing number of viruses that target the peroxisome to abrogate peroxisomal function.…”

Interferon‐stimulated gene products as regulators of central carbon metabolism

“…Together, these metabolites stimulate a balanced immune response via inflammatory eicosanoids, antigen cross-presentation, activation of NFAT and NF-jB and stimulation of formation of NO. This immunometabolic regulation of central carbon metabolism to stimulate a broad-spectrum immune response provides an explanation for the wide range of effects observed due to expression of RSAD2 (viperin) in many cell types: these include the broad-spectrum antiviral response [19], optimal Th2 cytokine production [93], which requires NFAT function [109], modulation of cellular lipid metabolism during human cytomegalovirus and influenza virus infections [110,111], induction of type-1 interferon production in plasmacytoid dendritic cells via a Toll-like receptor-mediated mechanism [112], interference with glucose homeostasis [26] and regulation of macrophage polarization [91]. Our analyses suggest that inhibition of GAPDH by the cellular innate immune response primes a broadspectrum immune response to viral infection.…”