Viral Pseudo-Enzymes Activate RIG-I via Deamidation to Evade Cytokine Production

• DOI: 10.1016/j.molcel.2015.01.036
• Publication Date: 2015-03-05T17:03:59Z
• Authors: Shanping He; Jun Zhao; Shanshan Song; Xiaojing He; Arlet Minassian; Yu Zhou; Junjie Zhang; Kevin Brulois; Yuqi Wang; Jackson Cabo; Ebrahim Zandi; Chengyu Liang; Jae U. Jung; Xuewu Zhang; Pinghui Feng
• Keywords: Molecular Mimicry; Cell Biology; Fibroblasts; Amides; Immunity, Innate; Cell Line; 3. Good health; DEAD-box RNA Helicases; Enzyme Activation; Mice; Gammaherpesvirinae; HEK293 Cells; Gene Expression Regulation; Animals; Cytokines; DEAD Box Protein 58; Humans; RNA, Viral; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; RNA, Small Interfering; Receptors, Immunologic; Molecular Biology; Immune Evasion

RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here, we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologs of phosphoribosylformylglycinamidine synthetase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homolog thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme.