|Herpesvirus is one of the most ubiquitous pathogens in nature. A remarkable propensity of all herpesviruses is their
ability to establish life-long persistent infection, known as latency. Not surprisingly, herpesviruses have evolved diverse
strategies to evade and harness cellular signaling, e.g., innate immune response. We have previously reported that gamma
herpesviruses utilize the mitochondrion antiviral signaling (MAVS) adaptor and IKKβ kinase to promote viral lytic replication.
Specifically, activated IKK phosphorylates viral key transcription factor (RTA) to enable viral gene expression. Additionally,
IKKβ was hijacked to induce the degradation of RelA, thereby terminating NF-κB activation and preventing antiviral cytokine
production. These findings highlight an intricate immune evasion strategy and suggest that gamma herpesviruses have
dedicated mechanism(s) to activate the MAVS-dependent signaling cascade.
Activation of pattern recognition receptors is crucial for host innate immune defense and RIG-I is a genuine RNA sensor.
We describe here a mechanism of RIG-I activation enabled by amidotransferase-mediated deamidation. To dissect herpesviral
immune evasion strategy, we discovered that viral homologues of phosphoribosylformyglycinamide synthase (PFAS), although
lacking intrinsic enzyme activity, recruited cellular PFAS to deamidate RIG-I. Accordingly, depletion or biochemical inhibition
of PFAS impaired RIG-I deamidation. Purified PFAS and viral homologues thereof deamidate RIG-I in vitro. Glutaminedeamidation
within the first CARD synergized with asparagine-deamidation within the ATPase domain to activate RIG-I. Our
findings show that viral pseudo enzymes and cellular PFAS activate RIG-I via deamidation, unveiling a new means by which a
pattern recognition receptor is activated by an enzyme and identifying a cellular protein deamidase.