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

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.

KDELR2 Competes with Measles Virus Envelope Proteins for Cellular Chaperones Reducing Their Chaperone-Mediated Cell Surface Transport

“…The receptors of the four C-terminal amino acids KDEL are located in the ER-Golgi intermediate compartment and cis-Golgi, where they catch KDEL-bearing proteins escaping from the ER and re-transport them to the ER lumen. In contrast to our findings with MV, KDEL receptors have been described to support the replication of dengue [12], Japanese encephalitis [13], and vaccinia virus [14]. In the case of dengue virus, this is probably due to the fact that the viral prM protein is a direct target of KDELR and that nascent dengue viruses bud into the lumen of the ER and are translocated to the Golgi [12].…”

“…For example, the dengue virus 1 (DENV1) prM protein interacts directly with KDELR1 and KDELR2, which supports transport of the viral envelope proteins to the plasma membrane [12]. JEV (Japanese encephalitis virus), another member of the Flavivirus family, is also dependent on KDELR1 mediated viral particle transport to the plasma membrane [13]. In the case of the vaccinia virus, host cellular membranes are delivered to virions by KDELRs and coatomer proteins [14].…”

Glucose-Regulated Protein 78 Interacts with Zika Virus Envelope Protein and Contributes to a Productive Infection

“…It was proposed previously that GRP78 could represent a broad anti-viral target [75], as it has been shown to be pro-viral for viruses beyond the flavivirus genus, including chikungunya virus, Ebola virus, measles virus, influenza virus, hepatitis B virus, enterovirus, retroviruses, and coronaviruses such as Middle East respiratory virus [75][76][77][78][79][80][81][82][83][84]. GRP78 is a multi-faceted protein with diverse roles during viral life cycles; it has been shown to act as a (co-)receptor, to facilitate protein trafficking, and to function as a chaperone.…”

Neuroinvasiveness of the MR766 strain of Zika virus in IFNAR-/- mice maps to prM residues conserved amongst African genotype viruses

“…A K21T substitution in the pr protein of dengue virus significantly reduced the positive charged-based interaction with KDEL receptors, an interaction required for efficient dengue virus egress from the cell [106]. The KDEL receptors are also required for efficient egress of Japanese encephalitis virus [107] and have also been associated with transcytosis in non-viral systems [108,109]. Efficient secretion of dengue virus requires binding of the pr protein to class II ADP-ribosylation factors (Arf4 and Arf5), which are required for KDEL receptor trafficking [110].…”