KDEL Receptors Assist Dengue Virus Exit from the Endoplasmic Reticulum

•Depletion of KDELR by siRNA reduces egress of DENV progeny•DENV1-3 structural protein prM interacts with KDELR in the ER•KDELR/prM interaction requires three positively charged amino acids at N terminus of prM•Disrupting this interaction inhibits DENV1 RSPs transport from the ER to the Golgi

SummaryMembrane receptors at the surface of target cells are key host factors for virion entry; however, it is unknown whether trafficking and secretion of progeny virus requires host intracellular receptors. In this study, we demonstrate that dengue virus (DENV) interacts with KDEL receptors (KDELR), which cycle between the ER and Golgi apparatus, for vesicular transport from ER to Golgi. Depletion of KDELR by siRNA reduced egress of both DENV progeny and recombinant subviral particles (RSPs). Coimmunoprecipitation of KDELR with dengue structural protein prM required three positively charged residues at the N terminus, whose mutation disrupted protein interaction and inhibited RSP transport from the ER to the Golgi. Finally, siRNA depletion of class II Arfs, which results in KDELR accumulation in the Golgi, phenocopied results obtained with mutagenized prME and KDELR knockdown. Our results have uncovered a function for KDELR as an internal receptor involved in DENV trafficking.

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