Viperin (Virus Inhibitory Protein, Endoplasmic Reticulum associated, INterferon inducible) is a recently recognized human radical S-adenosylmethionine (SAM) enzyme involved in cellular antiviral response. Radical SAM enzymes use SAM as a cofactor to generate the reactive 5’-deoxyadenosyl radical (5’dAdo) and all are very oxygen-sensitive. Viperin is conserved across all kingdoms of life, indicating its ancient and important role in the antiviral response. In animals, viperin functions in two ways: it synthesizes an antiviral nucleotide, 3’-deoxy-3’,4’-didehydro-CTP (ddhCTP) from cytidine triphosphate (CTP), that inhibits replication of some RNA viruses by acting as a viral polymerase chain terminator; it also acts as an important regulator of the antiviral response through interactions with numerous cellular and viral proteins. We recently used proteomic analysis to investigate the interactome of viperin. Multiple cholesterol biosynthetic enzymes were among the most enriched proteins, with lanosterol synthase (LS) and squalene monooxygenase (SM) being the top two hits. Many enveloped viruses require cholesterol-rich membranes to successfully bud from the cell and we have shown that over-expression of viperin inhibits cholesterol biosynthesis. Studies in our lab are directed towards understanding the regulatory effect on cholesterol biosynthesis that viperin may exert through its interactions with SM and LS. The proteomic analysis also identified several ubiquitin-conjugating enzymes in viperin’s interactome; indeed, viperin is known to promote the ubiquitin-dependent degradation of various cellular and viral proteins. Viperin also potentiates innate immune signaling pathway by activating the E3 ubiquitin ligase, TRAF6 to polyubiquitinate IRAK1. We have reconstituted the viperin-TRAF6 interaction in vitro to directly demonstrate viperin’s role in activating the innate immune signaling pathway. Our studies also implying a broader role for viperin as an activator of protein ubiquitination leading to proteasomal degradation pathway of its target proteins.

Viperin: A novel antiviral protein

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ACS Fall 2022

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