Caspase-12 controls West Nile virus infection via the viral RNA receptor RIG-I

Abstract

Caspase-12 has been shown to negatively modulate inflammasome signaling during bacterial infection. Its function in viral immunity, however, has not been characterized. We now report an important role for caspase-12 in controlling viral infection via the pattern-recognition receptor RIG-I. After challenge with West Nile virus (WNV), caspase-12-deficient mice had greater mortality, higher viral burden and defective type I interferon response compared with those of challenged wild-type mice. In vitro studies of primary neurons and mouse embryonic fibroblasts showed that caspase-12 positively modulated the production of type I interferon by regulating E3 ubiquitin ligase TRIM25–mediated ubiquitination of RIG-I, a critical signaling event for the type I interferon response to WNV and other important viral pathogens.

Japanese encephalitis virus NS1′ protein depends on pseudoknot secondary structure and is cleaved by caspase during virus infection and cell apoptosis

“…In ER, caspase-12 and human caspase-4 are dispensable for ERinduced apoptosis [45], but play a role in cell inflammatory response [37,44]. Evidence that caspase-12 controls WNV infection via retinoic acid-inducible gene I protein (RIG-I) and a downstream IFN pathway suggests new features of this caspase [46]. Unfortunately, the toxic effect of caspase-12 inhibitors for BHK-21 cells and the absence of commercial inhibitors of murine caspase-11, the homologous caspase of human caspase-4, did not allow identification of the caspase involved in NS1 0 cleavage.…”

West Nile Virus: Biology, Transmission, and Human Infection

“…Patients who mount a robust IFN-␣ response show lower viral loads, even before IgM seroconversion, concomitant with significant upregulation of IFN-␥ during the viremic phase (217). Permeability of the blood-brain barrier (BBB), which is enhanced by cytokine responses, has been shown in murine models to be critical to resistance to WNV infection (230), and elements which decrease the integrity of the BBB contribute to susceptibility to infection with WNV (7,226,227). Entry to the CNS may be afforded by trafficking of infected CD45 ϩ leukocytes and CD11b macrophages (218), T cells (228), or neutrophils (225).…”

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

“…Perhaps combined these studies indicate that sequential recruitment of RIG-I and TRIM25 to linear ubiquitin chains may function as a mechanism to regulate RIG-I induced IFN production. In another twist, caspase 12 has recently been shown to positively regulate RIG-I mediated IFN-b in response to West Nile virus infection, potentially via promoting the interaction between RIG-I and TRIM25, although the precise mechanism behind this is as yet unknown [71]. Given the role of IFNs in SLE, it remains to be seen whether TRIM25 levels or activity are altered in patients suffering this systemic autoimmune disease.…”