Human cytomegalovirus pUL37x1 induces the release of endoplasmic reticulum calcium stores

*Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014; and
^†Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010

Contributed by Thomas Shenk, October 23, 2006 (received for review October 16, 2006)

Abstract

The human CMV UL37x1-encoded protein, also known as the viral mitochondria-localized inhibitor of apoptosis, traffics to the endoplasmic reticulum and mitochondria of infected cells. It induces the fragmentation of mitochondria and blocks apoptosis. We demonstrate that UL37x1 protein mobilizes Ca²⁺ from the endoplasmic reticulum into the cytosol. This release is accompanied by cell rounding, cell swelling, and reorganization of the actin cytoskeleton, and these morphological changes can be substantially blocked by a Ca²⁺ chelating agent. The UL37x1-mediated release of Ca²⁺ from the endoplasmic reticulum likely has multiple consequences, including induction of the unfolded protein response, modulation of mitochondrial function, induction of mitochondrial fission, and protection against apoptotic stimuli.

Footnotes

^‡To whom correspondence should be addressed. E-mail: tshenk{at}princeton.edu
Author contributions: R.S.-F., A.M.C.-P., and T.S. designed research; R.S.-F. and J.G. performed research; J.G. and A.M.C.-P. contributed new reagents/analytic tools; R.S.-F., J.G., and T.S. analyzed data; and R.S.-F., A.M.C.-P., and T.S. wrote the paper.
The authors declare no conflict of interest.
Abbreviations:

ER,

endoplasmic reticulum;

SERCA,

sarcoendoplasmic reticulum Ca2+-ATPase;

BAPTA,

1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester;

hpi,

hours postinfection;

HCMV,

human CMV.