A KDEL Retrieval System for ER-Golgi Transport of Japanese Encephalitis Viral Particles.

Robert Wang,Han-Shan Chen,Yu-Jen Wu,Chih-Jung Chen

doi:10.3390/v8020044

Robert Wang, Han-Shan Chen + Show 2 more

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https://doi.org/10.3390/v8020044

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Abstract

Evidence has emerged that RNA viruses utilize the host secretory pathway for processing and trafficking mature viral particles and for exiting the infected cells. Upon completing the complex assembly process, the viral particles take advantage of the cellular secretory trafficking machinery for their intracellular trafficking toward the Golgi organelle and budding or export of virions. In this study, we showed that Japanese encephalitis virus (JEV)-induced extracellular GRP78 contains no KDEL motif using an anti-KDEL-specific antibody. Overexpression of the KDEL-truncated GRP78 in the GPR78 knocked down cells significantly reduced JEV infectivity, suggesting that the KDEL motif is required for GRP78 function in the release of JE viral particles. In addition, we demonstrated the KDELR protein, an ER-Golgi retrieval system component, is associated with viral envelope proteins and is engaged in the subcellular localization of viral particles in Golgi. More importantly, accumulation of intracellular virions was observed in the KDELR knocked down cells, indicating that the KDELR protein mediated the intracellular trafficking of JE viral particles. Altogether, we demonstrated that intracellular trafficking of JE assembled viral particles was mediated by the host ER-Golgi retrieval system prior to exit by the secretory pathway.

Highlights

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes human epidemic encephalitis; it is mostly found in Asian countries, including Japan, China, Taiwan, South Korea and India; and it leads to a 10% to 40% fatality rate [1]
Some reports have demonstrated that the cleavage of the carboxyl-terminal critical for secretory transport of GRP78 toward the cell surface [15]; our results indicated that the KDEL motif is critical for secretory transport of GRP78 toward the cell surface (15); our results cleavage of the KDEL, an endoplasmic reticulum (ER)-retention signal, is required for cytoplasmic GRP78 to participate in the indicated that the cleavage of the KDEL, an ER-retention signal, is required for cytoplasmic GRP78 folding, assembly and transport of viral particles during the virus infection cycle
We found that JE viral structural proteins bound to GRP78, an ER chaperone, through a KDEL receptor (KDELR)-related mechanism; the virus likely recruited the host ER retrieval system for assisting assembled viral particles in exiting from the ER and translocating to the Golgi complex for their subsequent exit from the cell

Summary

Introduction

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes human epidemic encephalitis; it is mostly found in Asian countries, including Japan, China, Taiwan, South Korea and India; and it leads to a 10% to 40% fatality rate [1]. The JEV genome is a single-stranded, positive-sense RNA comprising 10,976 nucleotides (nts) and containing a 51 capped structure, but no polyA tail at its 31 end. The transport and release of newly-assembled JE viral particles is a complex and dynamic process that involves hijacking host membrane transport systems, including the endoplasmic reticulum (ER) to the Golgi classic secretory pathway, by using viral structural proteins [2]. After viral envelope protein assembly and genome packaging at the site of an ER-derived membrane, viral particles exit the ER and traffic to a site of secondary envelopment considered to be trans-Golgi or endosomal membranes

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