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  • Original Article
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GRIM-19 associates with the serine protease HtrA2 for promoting cell death

Oncogene volume 26, pages 4842–4849 (2007)Cite this article

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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Author notes

  1. X Ma and S Kalakonda: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    X Ma, S Kalakonda & D V Kalvakolanu

  2. Laboratory of Immune Cell Biology, National Cancer Institute, Bethesda, MD, USA

    S M Srinivasula

  3. Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    S P Reddy

  4. Division of Hematology and Oncology, Lurie Cancer Center, Northwestern University, School of Medicine, Chicago, IL, USA

    L C Platanias

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  1. X Ma
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  2. S Kalakonda
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Correspondence to D V Kalvakolanu.

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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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