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.
Highlights
Measles virus (MV) replication is reduced by more than 90% in ectopically A3G expressing Vero cells [1]
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
To investigate the potential role of KDELR2 in the inhibition of MV replication, Vero cells were transduced with a role of KDELR2 in the A3G mediated inhibition of MV, KDELR2 levels were depleted in Vero-A3G
Summary
Measles virus (MV) replication is reduced by more than 90% in ectopically A3G expressing Vero cells [1]. We recently described that one of the A3G regulated host cell factors, REDD1 (regulated in development and DNA damage response-1), affects MV replication via regulation of mTORC1 [2]. Another host cell factor, KDELR2, was significantly increased upon the ectopic expression of A3G [2], requiring closer investigation. Activation of the seven-transmembrane KDEL receptors results in the activation of src family kinases coordinating the secretory pathway [4]. By this mechanism, chaperones regulate the maturation and fate of proteins to prevent excessive aggregation in the ER-Golgi network. Already identified in 1990, the complete functions of KDELR family proteins are Viruses 2019, 11, 27; doi:10.3390/v11010027 www.mdpi.com/journal/viruses
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