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

Wang, P., et al. 2010. Nature Immunology. 10:912-919.

Student: Yi-Jui Chuang (莊宜叡)                           Time:13:10-14:00, Nov. 24, 2010

Commentator: Dr. Yao Chang (張堯 博士)         Place: Room 601

Abstract

Caspase-12, a key caspase for endoplasmic reticulum stress-induced apoptosis, is a negative regulator of inflammasome signaling during bacterial infection (1,2). However, its function in viral immunity has not been characterized. In the present study, the authors demonstrated that caspase-12 is required for an effective innate immune response to West Nile virus (WNV) via regulation of the ubiquitination of retinoic acid inducible gene I (RIG-I). Mice lacking of caspase-12 were significantly more susceptible to WNV-induced lethality than control mice. Both interferon (Ifn)a and IfnbmRNA were significantly lower at day 2 after infection in the absence of caspase-12, and the concentration of IFN-b protein was significantly lower in Caspase12^-/- mice at day 4 after infection than in control mice. These data suggest caspase-12 has a dominant role in the type I IFN response. To further investigate the type I IFN signaling, mouse embryonic fibroblasts (MEFs) was used as in vitro model. After MEFs infected with WNV, lack of caspase-12 reduced RIG-I expression but not melanoma differentiation-associated gene 5 (Mda5) and MAVS. These results indicate that caspase-12 mediates its IFN signaling via RIG-I. The ubiquitination of RIG-I by E3 ubiquitinase tripartite motif-containing protein 25 (TRIM25) is an essential step for its signaling and promote type I IFN response (3). Overexpression of TRIM25 enhanced RIG-I-induced expression of Ifna and Ifnbtranscripts at a very early stage of WNV infection in wild-type cells but not in Caspase12^-/- cells. These results are collectively indicate that caspase-12 is required for an effective IFN response through the regulation of TRIM25-mediated ubiquitination of RIG-I.

References

1.      Nakagawa, T. et al. 2000. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 403:98-103.

2.      Saleh, M. et al. 2006. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature. 440:1064-1068.

3.      Gack, M.U. et al. 2007. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 446:916-920.