Human cytomegalovirus protein pUL38 induces ATF4 expression, inhibits persistent JNK phosphorylation, and suppresses endoplasmic reticulum stress-induced cell death.
The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the alpha subunit of eukaryotic initiation factor 2 (eIF-2alpha), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2alpha phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.
Xuan
Baoqin
B
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Qian
Zhikang
Z
Torigoi
Emi
E
Yu
Dong
D
D051701:Activating Transcription Factor 4 / Q000096:biosynthesis*; D036022:Capsid Proteins / Q000502:physiology*; D016923:Cell Death; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation
C497109:ATF4 protein, human; D036022:Capsid Proteins; D015852:Eukaryotic Initiation Factor-2; C539756:UL38 protein, human herpesvirus-5; D051701:Activating Transcription Factor 4; D048031:JNK Mitogen-Activated Protein Kinases