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

Abstract

Recently, we found that the cytidine deaminase APOBEC3G (A3G) inhibits measles (MV) replication. Using a microarray, we identified differential regulation of several host genes upon ectopic expression of A3G. One of the up-regulated genes, the endoplasmic reticulum (ER) protein retention receptor KDELR2, reduced MV replication ~5 fold when it was over-expressed individually in Vero and CEM-SS T cells. Silencing of KDELR2 in A3G-expressing Vero cells abrogated the antiviral activity induced by A3G, confirming its role as an A3G-regulated antiviral host factor. Recognition of the KDEL (Lys-Asp-Glu-Leu) motif by KDEL receptors initiates the retrograde transport of soluble proteins that have escaped the ER and play an important role in ER quality control. Although KDELR2 over-expression reduced MV titers in cell cultures, we observed no interaction between KDELR2 and the MV hemagglutinin (H) protein. Instead, KDELR2 retained chaperones in the ER, which are required for the correct folding and transport of the MV envelope glycoproteins H and fusion protein (F) to the cell surface. Our data indicate that KDELR2 competes with MV envelope proteins for binding to calnexin and GRP78/Bip, and that this interaction limits the availability of the chaperones for MV proteins, causing the reduction of virus spread and titers.

Glucose‐regulated protein (GRP78) is an important cell surface receptor for viral invasion, cancers, and neurological disorders

“…41 Furthermore, csGRP78 also acts as a port of entry for several additional viruses including the Japanese encephalitis virus, 42 human papillomavirus 16, 43 Tembusu virus, 44 and Measles virus. 45 Similarly, the receptor for the hepatitis B virus on the cell surface has not been identified; however, in the ER GRP78 interacts with the large surface protein of this virus in vitro and in vivo, 46 and regulates viral replication and survival in human hepatocytes. 46 A similar case is observed with the enterovirus 71 (EV71), where ER GRP78 is necessary for EV71 replication and infectivity in human brain microvascular endothelial cells, but it is not an attachment receptor for EV71 on the cell surface.…”

“…In stressed pancreatic beta cells, the secreted GRP78 acts as a proapoptotic ligand of csGRP78, promoting caspase mediated apoptosis that triggers a self-destructive feedback loop in type 1 diabetes. 45 Secreted GRP78 is also able to confer resistance to Bortezomib, a selective proteasome inhibitor, to several cell lines including endothelial, prostate cancer, murine melanoma, and myeloma cells, 77 and stimulates differentiation of bone marrow mesenchymal stem cells to cancer-associated fibroblasts. 78 GRP78 is also secreted by colon cancer cells through mechanisms involving increased GRP78 acetylation that limits its sorting to different compartments, thereby facilitating its secretion via exosomes in the tumor microenvironment, 79 where the acidic pH of the microenvironment accelerates the release of GRP78, promoting tumor progression in an autocrine/paracrine manner.…”

“…CsGRP78 is also a cell receptor for entry of the Borna disease virus, via a region located in the N‐terminal region, 40 and the hepatitis E virus, docking to a domain shared by the co‐chaperone MTJ1 in the csGRP78 SBD 41 . Furthermore, csGRP78 also acts as a port of entry for several additional viruses including the Japanese encephalitis virus, 42 human papillomavirus 16, 43 Tembusu virus, 44 and Measles virus 45 . Similarly, the receptor for the hepatitis B virus on the cell surface has not been identified; however, in the ER GRP78 interacts with the large surface protein of this virus in vitro and in vivo, 46 and regulates viral replication and survival in human hepatocytes 46 .…”

“…Pro‐inflammatory cytokines induce ER stress in pancreatic beta cells inducing secretion and plasma membrane translocation of GRP78. In stressed pancreatic beta cells, the secreted GRP78 acts as a proapoptotic ligand of csGRP78, promoting caspase mediated apoptosis that triggers a self‐destructive feedback loop in type 1 diabetes 45 . Secreted GRP78 is also able to confer resistance to Bortezomib, a selective proteasome inhibitor, to several cell lines including endothelial, prostate cancer, murine melanoma, and myeloma cells, 77 and stimulates differentiation of bone marrow mesenchymal stem cells to cancer‐associated fibroblasts 78 .…”

Morbilliviruses: Entry, Exit and Everything In-Between

“…From a more basic virology perspective two publications addressed interactions between the viral envelope proteins and the host cell. Tiwarekar et al identified competitive interactions between the host protein KDELR2, MeV F and H proteins, and molecular chaperones involved in endoplasmic reticulum processing [8]. Separately, research from my lab identified that morbillivirus H proteins are a target for the host-cell interferon stimulated protein BST2/tetherin [9].…”