1. ¹Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
2. ²Laboratory of Immune Cell Biology, National Cancer Institute, Bethesda, MD, USA
3. ³Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
4. ⁴Division of Hematology and Oncology, Lurie Cancer Center, Northwestern University, School of Medicine, Chicago, IL, USA

Correspondence: Professor DV Kalvakolanu, Department of Microbiology and Immunology, Greebaum Cancer Center, University of Maryland, School of Medicine, Baltimore MD 21201, USA. E-mail: dkalvako@umaryland.edu

⁵These two authors contributed equally to this work.

Received 7 July 2006; Revised 29 November 2006; Accepted 1 December 2006; Published online 12 February 2007.

Abstract

We have isolated a novel interferon (IFN)-retinoid regulated cell death regulatory protein genes associated with retinoid-IFN-induced mortality (GRIM)-19 earlier. To understand its mechanism of action, we have employed a yeast-two-hybrid screen and identified serine protease HtrA2 as its binding partner. GRIM-19 physically interacts with HtrA2 and augments cell death in an IFN/all-trans retinoic acid (RA)-dependent manner. In the presence of GRIM-19, the HtrA2-driven destruction of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP) is augmented. These interactions were disrupted by an human herpes virus-8 (HHV-8)-coded oncoprotein, vIRF1, and conferred resistance to IFN/RA-induced cell death. These data show a critical role of HtrA2 in a cytokine-induced cell death response for the first time and its inhibition by a viral protein.