Abstract
Viruses rely on host chaperone network to support their infection. In particular, the endoplasmic reticulum (ER) resident chaperones play key roles in synthesizing and processing viral proteins. Influx of a large amount of foreign proteins exhausts the folding capacity in ER and triggers the unfolded protein response (UPR). A fully-executed UPR comprises signaling pathways that induce ER folding chaperones, increase protein degradation, block new protein synthesis and may eventually activate apoptosis, presenting both opportunities and threats to the virus. Here, we define a role of the MHV-68M1 gene in differential modulation of UPR pathways to enhance ER chaperone production. Ectopic expression of M1 markedly induces ER chaperone genes and expansion of ER. The M1 protein accumulates in ER during infection and this localization is indispensable for its function, suggesting M1 acts from the ER. We found that M1 protein selectively induces the chaperon-producing pathways (IRE1, ATF6) while, interestingly, sparing the translation-blocking arm (PERK). We identified, for the first time, a viral factor capable of selectively intervening the initiation of ER stress signaling to induce chaperon production. This finding provides a unique opportunity of using viral protein as a tool to define the activation mechanisms of individual UPR pathways.
Highlights
The endoplasmic reticulum (ER) plays a central role in protein synthesis, folding, assembly with the help of a large set of ER-resident chaperones[2]
In order to systematically identify viral components of murine gamma-herpesvirus 68 (MHV-68) that modulate the expression of ER chaperone genes, we conducted a genomic viral open reading frame (ORF) screen using a reporter system based on GRP78 expression
We found that the ER-localized M1 functions through selective activation of the chaperone-inducing branches (IRE1 and activating transcription factor-6 (ATF6)) of unfolded protein response (UPR) pathways while sparing the translation-inhibiting cascade (PERK)
Summary
The endoplasmic reticulum (ER) plays a central role in protein synthesis, folding, assembly with the help of a large set of ER-resident chaperones[2]. Three distinct UPR signaling pathways have been identified, with each arm individually mediated by three ER membrane-bound stress sensors: inositol-requiring protein-I (IRE1), activating transcription factor-6 (ATF6) and protein kinase RNA (PKR)-like ER kinase (PERK). It remains controversial on how the three signaling proteins sense the ER stress[8]. Recent work indicated that the each transmembrane signal transducer may possess unique properties in sensing the stress, and the state of chaperone association is not sufficient to determine their activation statues[9]. Unlike human gamma-herpesvirus, MHV-68 is capable of establishing robust infection in vitro and in vivo[23]
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