Japanese encephalitis virus replication is negatively regulated by autophagy and occurs on LC3-I- and EDEM1-containing membranes

Manish S., Sankar B., Minu N., Manpreet K., Vikas S., Vishal G., Renu K., Malik Z A., Sudhanshu V. & Manjula K., Autophagy (2014) 10(9):1637-51

Speaker: Po-Jung Fu (傅柏蓉)                                                     Time: 15:00~16:00, Apr, 2015.

Commentator: Dr. Guey-Chuen Perng (彭貴春 老師)                Place: Room 601

Abstract:

     Positive sense RNA [(+) RNA] viruses subvert host factors to form virus replication complex (VRC). VRC concentrates virus and host factors to facilitate virus RNA synthesis and protects virus from recognizing by host immune system [1]. Coronaviruses (CoV) remodels endoplasimic reticulum (ER) membrane to form a double membrane vesicle (DMV). CoV translocases its replication and transcription factors to the DMV. [2]. DMV formation results in CoV interference of ER-associating degradation (ERAD) tuning, which is a process to maintain ER at steady state. Under normal growth conditions, EDEM-1, a crucial regulator of ERAD, was segregated from bulk ER to LC3-Ⅰ containing vesicle (known as EDEMOsomes) and rapidly degraded to keep EDEM-1at low level. However, (+) RNA viruses hijack this pathway to form DMV, which serves as virus replication platform. Japanese encephalitis virus (JEV) is a (+) RNA virus and belongs toFlaviviridae. It causes severe neurologic manifestation. Although vaccination is efficient way to prevent disease, epidemic or endemic outbreak still occurs. The fatality of JEV ranges from 20% to 30%, with neurologic or psychiatric sequelae observed in 30~50% survivors [4]. In this paper, the authors found that in JEV infected neuronal cells, autophagy deficiency increased viral replication and cell susceptibility to virus infection. Their further study showed that JEV replication complex associates with EDEMOsomes, which is similar to the report on other (+) RNA viruses. However, the virus replication complex did not colocalize with LC3-GFP, which represents autophagosome LC3-Ⅱ. In conclusion, this paper suggests that 1. JEV infection induces autophagy which negatively regulates virus replication, 2. JEV utilizes JEV utilizes EDEMosomes that decorated with LC3-Ⅰprotein as replication complex.

References:

1.  Nagy, P.D. and Pogany J., The dependence of viral RNA replication on co-opted host factors. Nat Rev Microbiol (2012) 10(2): 137-49.

2.  Reggiori, F., de Haan C. A., and Molinari M., Unconventional use of LC3 by coronaviruses through the alleged subversion of the ERAD tuning pathway. Viruses (2011) 3(9): 1610-23.

3.  Cali, T., Galli, C., Olivari, S. and Molinari, M., Segregation and rapid turnover of EDEM1 by an autophagy-like mechanism modulates standard ERAD and folding activities. Biochem Biophys Res Commun, 2008. 371(3): 405-10.

4.  Wang, H. and Liang G., Epidemiology of Japanese encephalitis: past, present, and future prospects. Ther Clin Risk Manag (2015) 11: 435-48.