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Human cytomegalovirus UL38 protein blocks apoptosis. J Virol 2007 Apr;81(7):3109-23

Date

01/05/2007

Pubmed ID

17202209

Pubmed Central ID

PMC1866066

DOI

10.1128/JVI.02124-06

Scopus ID

2-s2.0-33947399734 (requires institutional sign-in at Scopus site)   134 Citations

Abstract

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.

Author List

Terhune S, Torigoi E, Moorman N, Silva M, Qian Z, Shenk T, Yu D

Author

Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Apoptosis
Base Sequence
Capsid Proteins
Cell Differentiation
Cell Shape
Cells, Cultured
Cytomegalovirus
DNA, Viral
Fibroblasts
Gene Deletion
Gene Expression
Genome, Viral
Humans
Mutation
Viral Fusion Proteins
Virus Replication