Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production.
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.
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Shanping
S
He
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Jun
J
Zhao
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Shanshan
S
Song
Department of Pharmacology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75039, USA.
Xiaojing
X
He
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Arlet
A
Minassian
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Yu
Y
Zhou
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Junjie
J
Zhang
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Kevin
K
Brulois
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Yuqi
Y
Wang
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Jackson
J
Cabo
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Ebrahim
E
Zandi
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Chengyu
C
Liang
Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Jae U
JU
Jung
Department of Pharmacology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75039, USA.
Xuewu
X
Zhang
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.
Pinghui
P
Feng
D000577:Amides / Q000378:metabolism; D000818:Animals; D019733:Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000821:virology; D018142:Gammaherpesvirinae / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D007113:Immunity, Innate; D051379:Mice; D018716:Molecular Mimicry; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
D000577:Amides; D016207:Cytokines; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D014764:Viral Proteins; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D019733:Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; C022385:phosphoribosylformylglycinamidine synthetase