Human cytomegalovirus infection activates and regulates the unfolded protein response.
Viral infection causes stress to the endoplasmic reticulum. The response to endoplasmic reticulum stress, known as the unfolded protein response (UPR), is designed to eliminate misfolded proteins and allow the cell to recover by attenuating translation and upregulating the expression of chaperones, degradation factors, and factors that regulate the cell's metabolic and redox environment. Some consequences of the UPR (e.g., expression of chaperones and regulation of the metabolism and redox environment) may be advantageous to the viral infection; however, translational attenuation would not. Thus, viruses may induce mechanisms which modulate the UPR, maintaining beneficial aspects and suppressing deleterious aspects. We demonstrate that human cytomegalovirus (HCMV) infection induces the UPR but specifically regulates the three branches of UPR signaling, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE-1), to favor viral replication. HCMV infection activated the eIF2alpha kinase PERK; however, the amount of phosphorylated eIF2alpha was limited and translation attenuation did not occur. Interestingly, translation of select mRNAs, which is dependent on eIF2alpha phosphorylation, did occur, including the transcription factor ATF4, which activates genes which may benefit the infection. The endoplasmic reticulum stress-induced activation of the transcription factor ATF6 was suppressed in HCMV-infected cells; however, specific chaperone genes, normally activated by ATF6, were activated by a virus-induced, ATF6-independent mechanism. Lastly, HCMV infection activated the IRE-1 pathway, as indicated by splicing of Xbp-1 mRNA. However, transcriptional activation of the XBP-1 target gene EDEM (ER degradation-enhancing alpha-mannosidase-like protein, a protein degradation factor) was inhibited. These results suggest that, although HCMV infection induces the unfolded protein response, it modifies the outcome to benefit viral replication.
Isler
Jennifer A
JA
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, USA.
Skalet
Alison H
AH
Alwine
James C
JC
D051701:Activating Transcription Factor 4; D051702:Activating Transcription Factor 6; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics; D014176:Protein Biosynthesis; D011489:Protein Denaturation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012326:RNA Splicing; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
D051701:Activating Transcription Factor 4; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C497111:ATF6 protein, human; C000605543:XBP1 protein, human; C403982:ERN2 protein, human