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Journal of Virology, December 2005, p. 14923-14932, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14923-14932.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Contribution of GADD45 Family Members to Cell Death Suppression by Cellular Bcl-x_L and Cytomegalovirus vMIA

Geoffrey B. Smith and Edward S. Mocarski^*

Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305-5124

Received 1 June 2005/ Accepted 13 September 2005

Mammalian cells and viruses encode inhibitors of programmed cell death that localize to mitochondria and suppress apoptosis initiated by a wide variety of inducers. Mutagenesis was used to probe the role of a predicted -helical region within the hydrophobic antiapoptotic domain (AAD) of cytomegalovirus vMIA, the UL37x1 gene product. This region was found to be essential for cell death suppression activity. A screen for proteins that interacted with the AAD of functional vMIA but that failed to interact with mutants identified growth arrest and DNA damage 45 (GADD45), a cell cycle regulatory protein activated by genotoxic stress, as a candidate cellular binding partner. GADD45 interaction required the AAD -helical character that also dictated GADD45-mediated enhancement of death suppression. vMIA mutants that failed to interact with GADD45 were completely nonfunctional in cell death suppression, and any of the three GADD45 family members (GADD45, GADD45ß/MyD118, or GADD45/OIG37/CR6/GRP17) was able to cooperate with vMIA; however, none influenced cell death when introduced into cells alone. GADD45 was found to increase vMIA protein levels comparably to treatment with protease inhibitors MG132 and ALLN. Targeted short interfering RNA knockdown of all three GADD45 family members maximally reduced vMIA activity, and this reduction was abrogated by additional GADD45. Interestingly, GADD45 family members were also able to bind and enhance cell death suppression by Bcl-x_L, a member of the Bcl-2 family of cell death suppressors, suggesting a direct cooperative link between apoptosis and the proteins that regulate the DNA damage response.

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* Corresponding author. Mailing address: Department of Microbiology & Immunology, Fairchild Science Building, 299 Campus Dr., Stanford University School of Medicine, Stanford, CA 94305-5124. Phone: (650) 723-6435. Fax: (650) 723-1606. E-mail: mocarski{at}stanford.edu.

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Journal of Virology, December 2005, p. 14923-14932, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14923-14932.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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