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Edited by Thomas E. Shenk, Princeton University, Princeton, NJ, and approved July 23, 2019 (received for review April 30, 2019)
Significance
Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and the most common infectious cause of birth defects. Although HCMV is not a generally accepted cause of cancer, it shares similarities to cancer-causing viruses: It dysregulates the cell cycle, activates the DNA damage response, and suppresses apoptosis. However, causes and consequences of these viral properties remain poorly understood. Here we show that HCMV activates caspase-2, an apoptosis-related enzyme activated by DNA damage and abnormal mitosis, in a strain-specific manner. Caspase-2 activation depends on envelope glycoprotein B variants with increased fusogenicity, which facilitate viral entry, promote cell fusion, and affect genome stability. These results suggest that specific glycoprotein B variants might affect HCMV transmission and pathogenicity.
Abstract
Human cytomegalovirus (HCMV), like many other DNA viruses, can cause genome instability and activate a DNA damage response (DDR). Activation of ataxia-telangiectasia mutated (ATM), a kinase activated by DNA breaks, is a hallmark of the HCMV-induced DDR. Here we investigated the activation of caspase-2, an initiator caspase activated in response to DNA damage and supernumerary centrosomes. Of 7 HCMV strains tested, only strain AD169 activated caspase-2 in infected fibroblasts. Treatment with an ATM inhibitor or inactivation of PIDD or RAIDD inhibited caspase-2 activation, indicating that caspase-2 was activated by the PIDDosome. A set of chimeric HCMV strains was used to identify the genetic basis of this phenotype. Surprisingly, we found a single nucleotide polymorphism within the AD169 UL55 ORF, resulting in a D275Y amino acid exchange within glycoprotein B (gB), to be responsible for caspase-2 activation. As gB is an envelope glycoprotein required for fusion with host cell membranes, we tested whether gB(275Y) altered viral entry into fibroblasts. While entry of AD169 expressing gB(275D) proceeded slowly and could be blocked by a macropinocytosis inhibitor, entry of wild-type AD169 expressing gB(275Y) proceeded more rapidly, presumably by envelope fusion with the plasma membrane. Moreover, gB(275Y) caused the formation of syncytia with numerous centrosomes, suggesting that cell fusion triggered caspase-2 activation. These results suggest that gB variants with increased fusogenicity accelerate viral entry, cause cell fusion, and thereby compromise genome stability. They further suggest the ATM-PIDDosome-caspase-2 signaling axis alerts the cell of potentially dangerous cell fusion.
Footnotes
- ↵1To whom correspondence may be addressed. Email: wolfram.brune{at}leibniz-hpi.de.
Author contributions: J.T. and W.B. designed research; J.T., G.F., and E.O. performed research; R.J.L. contributed new reagents/analytic tools; J.T., G.F., E.O., and W.B. analyzed data; and J.T. and W.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1907447116/-/DCSupplemental.
Published under the PNAS license.
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Human cytomegalovirus glycoprotein B variants affect viral entry, cell fusion, and genome stability
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