Cytomegalovirus downregulates IRE1 to repress the unfolded protein response.
During viral infection, a massive demand for viral glycoproteins can overwhelm the capacity of the protein folding and quality control machinery, leading to an accumulation of unfolded proteins in the endoplasmic reticulum (ER). To restore ER homeostasis, cells initiate the unfolded protein response (UPR) by activating three ER-to-nucleus signaling pathways, of which the inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved. To reduce ER stress, the UPR decreases protein synthesis, increases degradation of unfolded proteins, and upregulates chaperone expression to enhance protein folding. Cytomegaloviruses, as other viral pathogens, modulate the UPR to their own advantage. However, the molecular mechanisms and the viral proteins responsible for UPR modulation remained to be identified. In this study, we investigated the modulation of IRE1 signaling by murine cytomegalovirus (MCMV) and found that IRE1-mediated mRNA splicing and expression of the X-box binding protein 1 (XBP1) is repressed in infected cells. By affinity purification, we identified the viral M50 protein as an IRE1-interacting protein. M50 expression in transfected or MCMV-infected cells induced a substantial downregulation of IRE1 protein levels. The N-terminal conserved region of M50 was found to be required for interaction with and downregulation of IRE1. Moreover, UL50, the human cytomegalovirus (HCMV) homolog of M50, affected IRE1 in the same way. Thus we concluded that IRE1 downregulation represents a previously undescribed viral strategy to curb the UPR.
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
Sebastian
S
Stahl
Julia M
JM
Burkhart
Florian
F
Hinte
Boaz
B
Tirosh
Hermine
H
Mohr
René P
RP
Zahedi
Albert
A
Sickmann
Zsolt
Z
Ruzsics
Matthias
M
Budt
Wolfram
W
Brune
D000818:Animals; D002461:Cell Line, Transformed; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004722:Endoribonucleases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018146:Muromegalovirus / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D015678:Viral Structural Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases