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.
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Abbreviations
- FL:
-
full length
- GFP:
-
green fluorescent protein
- GRIM:
-
genes associated with retinoid-IFN-induced mortality
- HHV8:
-
human herpesvirus 8
- Htr:
-
high-temperature-resistant
- IFN:
-
interferon
- NB:
-
Northern blot
- RA:
-
all-trans retinoic acid
- STAT:
-
signal transducing activator of transcription
- vIRF1:
-
viral interferon regulatory factor 1
- WB:
-
Western blot
- XIAP:
-
X-linked inhibitor of apoptosis
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Acknowledgements
DVK thanks National Cancer Institute for grant support CA105005. We also thank Patrick Moore, Emad Alnemri and Margaret Offerman for providing the reagents used in this study.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Ma, X., Kalakonda, S., Srinivasula, S. et al. GRIM-19 associates with the serine protease HtrA2 for promoting cell death. Oncogene 26, 4842–4849 (2007). https://doi.org/10.1038/sj.onc.1210287
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DOI: https://doi.org/10.1038/sj.onc.1210287
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