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Mol Cell. 2015 Apr 2;58(1):134-46. doi: 10.1016/j.molcel.2015.01.036. Epub 2015 Mar 5.

Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production.

Author information

1
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
2
Department of Pharmacology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75039, USA.
3
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. Electronic address: pinghui.feng@usc.edu.

Abstract

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.

PMID:
25752576
PMCID:
PMC4385502
DOI:
10.1016/j.molcel.2015.01.036
[Indexed for MEDLINE]
Free PMC Article

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