A promiscuous inflammasome sparks replication of a common tumor virus, 2020, Burton et al

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A promiscuous inflammasome sparks replication of a common tumor virus
Eric M. Burton, Raphaela Goldbach-Mansky, Sumita Bhaduri-McIntosh

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.

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Inflammasomes are intracellular multiprotein oligomers that form in response to cell-intrinsic and cell-extrinsic threats.

The inflammasome may be activated by cell-intrinsic damage signals such as reactive oxygen species (ROS), lysosomal instability, and changes in intracellular electrolyte levels. Importantly, as a component of the innate immune system, inflammasome sensors detect foreign molecules, thus forming the first line of defense against infections.

As a herpesvirus that not only persists in its host but also causes cancer, Epstein-Barr virus (EBV) is a master manipulator of its host.

Importantly, we find that high glucose functions through the NLRP3 inflammasome to disrupt EBV quiescence

While herpesviruses and other viruses have been found to parry host defense mechanisms during different stages of infection, the present findings distinctly demonstrate a virus utilizing an inflammasome to directly trigger its replication. Indeed, to persist, the most prevalent human cancer-causing virus has tied its exit strategy to the most promiscuous danger-sensing mechanism in the cell

However, our findings indicate that, compared to healthy individuals, episodes of hyperglycemia in the context of chronic NLRP3 activation during diabetes may cause greater dysregulation of EBV in B lymphocytes, suggesting connections between diabetes, hyperglycemia, and EBV-related pathology.

 

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See also SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein (2022).