Skip to Content
Merck

A promiscuous inflammasome sparks replication of a common tumor virus.

Proceedings of the National Academy of Sciences of the United States of America (2020-01-11)
Eric M Burton, Raphaela Goldbach-Mansky, Sumita Bhaduri-McIntosh
ABSTRACT

Viruses activate inflammasomes but then subvert resulting inflammatory responses to avoid elimination. We asked whether viruses could instead use such activated or primed inflammasomes to directly aid their propagation and spread. Since herpesviruses are experts at coopting cellular functions, we investigated whether Epstein-Barr virus (EBV), an oncoherpesvirus, exploits inflammasomes to activate its replicative or lytic phase. Indeed, our experiments reveal that EBV exploits several inflammasome sensors to actually activate its replicative phase from quiescence/latency. In particular, TXNIP, a key inflammasome intermediary, causes assembly of the NLRP3 inflammasome, resulting in caspase-1-mediated depletion of the heterochromatin-inducing epigenetic repressor KAP1/TRIM28 in a subpopulation of cells. As a result, only TXNIPhiKAP1lo cells, that is, in a primed/prolytic state, turn expression of the replication/lytic/reactivation switch protein on to enter the replicative phase. Our findings 1) demonstrate that EBV dovetails its escape strategy to a key cellular danger-sensing mechanism, 2) indicate that transcription may be regulated by KAP1 abundance aside from canonical regulation through its posttranslational modification, 3) mechanistically link diabetes, which frequently activates the NLRP3 inflammasome, to deregulation of a tumor virus, and 4) demonstrate that B lymphocytes from NOMID (neonatal onset multisystem inflammatory disease) patients who have NLRP3 mutations and suffer from hyperactive innate responses are defective in controlling a herpesvirus.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium butyrate, 98%
Sigma-Aldrich
Valproic acid sodium salt, 98%
Sigma-Aldrich
5-Aza-2′-deoxycytidine, ≥97%
Sigma-Aldrich
Anti-EBNA2 Antibody, clone R3, clone R3, from rat
Sigma-Aldrich
Anti-EBV EA-D-p52/50 Antibody, clone R3, clone R3, Chemicon®, from mouse
Sigma-Aldrich
Rat IgG2a Negative Control, clone 2A3, Azide Free Antibody, clone 2A3, from rat, purified by affinity chromatography
Sigma-Aldrich
Goat Anti-Rabbit IgG Antibody, (H+L) HRP conjugate, 1 mg/mL, Chemicon®
Sigma-Aldrich
Anti-Mouse IgG (whole molecule)–FITC antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-GFP, N-terminal antibody produced in rabbit, ~1.0 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Goat Anti-Mouse IgG Antibody, (H+L) HRP conjugate, 1 mg/mL, Chemicon®
Sigma-Aldrich
Mouse IgG1 Negative Control Antibody, clone 1E2.2, clone 1E2.2, 1 mg/mL, Chemicon®