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M1 of Murine Gamma-Herpesvirus 68 Induces Endoplasmic Reticulum Chaperone Production.

Feng J, Gong D, Fu X, Wu TT, Wang J, Chang J, Zhou J, Lu G, Wang Y, Sun R - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095.

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.

No MeSH data available.


Related in: MedlinePlus

M1 induces ER expansion.293T cells were transfected with vector control (A) or plasmids encoding M1 (B) or M3 (C) for 24 hours, and were prepared for electron microscopy analysis. Arrows point to representative ER.
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f2: M1 induces ER expansion.293T cells were transfected with vector control (A) or plasmids encoding M1 (B) or M3 (C) for 24 hours, and were prepared for electron microscopy analysis. Arrows point to representative ER.

Mentions: In addition to increased production of GRP78, we also observed significantly enhanced gene expression of the other two major UPR chaperones GRP94 and ERdj4 in the presence of M1 (Fig. 1D). These findings directed our attention to the changes in the ER morphology. We speculated that in order to accommodate the newly-synthesized folding machineries, the amount or the size of the ER must have changed dramatically as described previously32. Indeed, electron microscopy analysis revealed a massive expansion of the ER in the M1-expressing cells as compared to cells transfected with the M3 plasmid or the control vector (Fig. 2).


M1 of Murine Gamma-Herpesvirus 68 Induces Endoplasmic Reticulum Chaperone Production.

Feng J, Gong D, Fu X, Wu TT, Wang J, Chang J, Zhou J, Lu G, Wang Y, Sun R - Sci Rep (2015)

M1 induces ER expansion.293T cells were transfected with vector control (A) or plasmids encoding M1 (B) or M3 (C) for 24 hours, and were prepared for electron microscopy analysis. Arrows point to representative ER.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663489&req=5

f2: M1 induces ER expansion.293T cells were transfected with vector control (A) or plasmids encoding M1 (B) or M3 (C) for 24 hours, and were prepared for electron microscopy analysis. Arrows point to representative ER.
Mentions: In addition to increased production of GRP78, we also observed significantly enhanced gene expression of the other two major UPR chaperones GRP94 and ERdj4 in the presence of M1 (Fig. 1D). These findings directed our attention to the changes in the ER morphology. We speculated that in order to accommodate the newly-synthesized folding machineries, the amount or the size of the ER must have changed dramatically as described previously32. Indeed, electron microscopy analysis revealed a massive expansion of the ER in the M1-expressing cells as compared to cells transfected with the M3 plasmid or the control vector (Fig. 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095.

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.

No MeSH data available.


Related in: MedlinePlus