Human cytomegalovirus UL38 protein blocks apoptosis.
Apoptosis is an innate cellular defense response to viral infection. The slow-replicating human cytomegalovirus (HCMV) blocks premature death of host cells prior to completion of the infection cycle. In this study, we report that the HCMV UL38 gene encodes a cell death inhibitory protein. A mutant virus lacking the pUL38 coding sequence, ADdlUL38, grew poorly in human fibroblasts, failed to accumulate viral DNA to wild-type levels, and induced excessive death of infected cells. Cells expressing pUL38 were resistant to cell death upon infection and effectively supported the growth of ADdlUL38. Cells infected with the pUL38-deficient virus showed morphological changes characteristic of apoptosis, including cell shrinkage, membrane blebbing, vesicle release, and chromatin condensation and fragmentation. The proteolytic cleavage of two key enzymes involved in apoptosis, namely, caspase 3 and poly(ADP-ribose) polymerase, was activated upon ADdlUL38 infection, and the cleavage was blocked in cells expressing pUL38. The pan-caspase inhibitor Z-VAD-FMK largely restored the growth of ADdlUL38 in normal fibroblasts, indicating that the defective growth of the mutant virus mainly resulted from premature death of host cells. Furthermore, cells expressing pUL38 were resistant to cell death induced by a mutant adenovirus lacking the antiapoptotic E1B-19K protein or by thapsigargin, which disrupts calcium homeostasis in the endoplasmic reticulum. Taken together, these results indicate that the HCMV protein pUL38 suppresses apoptosis, blocking premature death of host cells to facilitate efficient virus replication.
Terhune
Scott
S
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Torigoi
Emi
E
Moorman
Nathaniel
N
Silva
Maria
M
Qian
Zhikang
Z
Shenk
Thomas
T
Yu
Dong
D
D017209:Apoptosis; D001483:Base Sequence; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D048430:Cell Shape; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics; D005347:Fibroblasts; D017353:Gene Deletion; D015870:Gene Expression; D016679:Genome, Viral / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D036022:Capsid Proteins; D004279:DNA, Viral; C539756:UL38 protein, human herpesvirus-5; D014760:Viral Fusion Proteins