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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

A scheme illustrating the effects of M1 on UPR signaling pathways.Our data demonstrate that the ER-localized M1 activates the IRE1 and ATF6 branches of UPR but spare the PERK axis to enhance the production of ER chaperone proteins.
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f7: A scheme illustrating the effects of M1 on UPR signaling pathways.Our data demonstrate that the ER-localized M1 activates the IRE1 and ATF6 branches of UPR but spare the PERK axis to enhance the production of ER chaperone proteins.

Mentions: M1 is a viral gene unique to MHV-68. Previous study has reported that disruption of the M1 gene led to enhanced reactivation of the virus in in vivo infection24. It was later reported by the same group that secreted M1 protein act as a viral superantigen and is responsible for Vβ4+ CD8+ T cell stimulation during MHV-68 infection in mice28. However, it has not been fully elucidated whether M1 plays a role inside the host cell. Here we discovered a novel function for the intracellular M1 protein. We found that M1 differentially modulate the UPR signaling cascades and preferentially induces the two chaperone-producing branches to activate ER chaperone expression. Specifically, the M1 protein stimulates the IRE1 and the ATF6 axes but spares the PERK pathway of UPR signaling (Fig. 7). It is of interest that the virus selectively acts on the beneficial aspects of the UPR program while avoiding the detrimental features. One possible explanation is that the virus takes advantage of different stress sensing or activation mechanisms deployed by the three ER transmembrane sensors (i.e. IRE1, ATF6 and PERK). Although it is still unclear how these signaling proteins sense the ER stress, a recent study used the three-dimensional structure analysis to demonstrate that IRE1 activation is actually caused by direct binding to the unfolded proteins rather than by chaperone association as suggested earlier on9. This finding implicates that the three branches of UPR signaling network may be distinctly modulated at the initiation stage. We propose that certain undefined properties in the M1 protein leads to the differentiated modulation on the UPR sensors. Therefore, using M1 as a tool may offer a unique opportunity to dissect the mechanism underlying UPR sensing and regulation.


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)

A scheme illustrating the effects of M1 on UPR signaling pathways.Our data demonstrate that the ER-localized M1 activates the IRE1 and ATF6 branches of UPR but spare the PERK axis to enhance the production of ER chaperone proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: A scheme illustrating the effects of M1 on UPR signaling pathways.Our data demonstrate that the ER-localized M1 activates the IRE1 and ATF6 branches of UPR but spare the PERK axis to enhance the production of ER chaperone proteins.
Mentions: M1 is a viral gene unique to MHV-68. Previous study has reported that disruption of the M1 gene led to enhanced reactivation of the virus in in vivo infection24. It was later reported by the same group that secreted M1 protein act as a viral superantigen and is responsible for Vβ4+ CD8+ T cell stimulation during MHV-68 infection in mice28. However, it has not been fully elucidated whether M1 plays a role inside the host cell. Here we discovered a novel function for the intracellular M1 protein. We found that M1 differentially modulate the UPR signaling cascades and preferentially induces the two chaperone-producing branches to activate ER chaperone expression. Specifically, the M1 protein stimulates the IRE1 and the ATF6 axes but spares the PERK pathway of UPR signaling (Fig. 7). It is of interest that the virus selectively acts on the beneficial aspects of the UPR program while avoiding the detrimental features. One possible explanation is that the virus takes advantage of different stress sensing or activation mechanisms deployed by the three ER transmembrane sensors (i.e. IRE1, ATF6 and PERK). Although it is still unclear how these signaling proteins sense the ER stress, a recent study used the three-dimensional structure analysis to demonstrate that IRE1 activation is actually caused by direct binding to the unfolded proteins rather than by chaperone association as suggested earlier on9. This finding implicates that the three branches of UPR signaling network may be distinctly modulated at the initiation stage. We propose that certain undefined properties in the M1 protein leads to the differentiated modulation on the UPR sensors. Therefore, using M1 as a tool may offer a unique opportunity to dissect the mechanism underlying UPR sensing and regulation.

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