Human cytomegalovirus infection activates and regulates the unfolded protein response

Jennifer A. Isler, Alison Skalet, James C. Alwine

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

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 eIF2α kinase PERK; however, the amount of phosphorylated eIF2α was limited and translation attenuation did not occur. Interestingly, translation of select mRNAs, which is dependent on eIF2α 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 α-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.

Original languageEnglish (US)
Pages (from-to)6890-6899
Number of pages10
JournalJournal of Virology
Volume79
Issue number11
DOIs
StatePublished - Jun 2005
Externally publishedYes

Fingerprint

Human herpesvirus 5
unfolded protein response
Unfolded Protein Response
Activating Transcription Factor 6
Cytomegalovirus Infections
transcription factors
Endoplasmic Reticulum Stress
endoplasmic reticulum
translation (genetics)
phosphotransferases (kinases)
Phosphotransferases
Inositol
Virus Diseases
virus replication
Oxidation-Reduction
Activating Transcription Factor 4
Mannosidases
mannosidases
infection
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Human cytomegalovirus infection activates and regulates the unfolded protein response. / Isler, Jennifer A.; Skalet, Alison; Alwine, James C.

In: Journal of Virology, Vol. 79, No. 11, 06.2005, p. 6890-6899.

Research output: Contribution to journalArticle

Isler, Jennifer A. ; Skalet, Alison ; Alwine, James C. / Human cytomegalovirus infection activates and regulates the unfolded protein response. In: Journal of Virology. 2005 ; Vol. 79, No. 11. pp. 6890-6899.
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