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Published online January 7, 2008
doi:10.1083/jcb.200709030
The Journal of Cell Biology, Vol. 180, No. 1, 113-127
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Mazroui et al.
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Article

 Caspase-mediated cleavage of HuR in the cytoplasm contributes to pp32/PHAP-I regulation of apoptosis

Rachid Mazroui1, Sergio Di Marco1, Eveline Clair1, Christopher von Roretz1, Scott A. Tenenbaum3,4, Jack D. Keene5, Maya Saleh2, and Imed-Eddine Gallouzi1

1 Department of Biochemistry and 2 Department of Medicine, Division of Critical Care, McGill University Health Center, McGill University, Montreal, Quebec H3G 146, Canada
3 Department of Biomedical Sciences, Gen*NY*Sis Center for Excellence in Cancer Genomics, and 4 Center for Functional Genomics, University at Albany, State University of New York, Albany, NY 12144
5 Department of Molecular Genetics and Microbiology, Center for RNA Biology, Duke University, Durham, NC 27710

Correspondence to Imed-Eddine Gallouzi: imed.gallouzi{at}mcgill.ca

The RNA-binding protein HuR affects cell fate by regulating the stability and/or the translation of messenger RNAs that encode cell stress response proteins. In this study, we delineate a novel regulatory mechanism by which HuR contributes to stress-induced cell death. Upon lethal stress, HuR translocates into the cytoplasm by a mechanism involving its association with the apoptosome activator pp32/PHAP-I. Depleting the expression of pp32/PHAP-I by RNA interference reduces both HuR cytoplasmic accumulation and the efficiency of caspase activation. In the cytoplasm, HuR undergoes caspase-mediated cleavage at aspartate 226. This cleavage activity is significantly reduced in the absence of pp32/PHAP-I. Substituting aspartate 226 with an alanine creates a noncleavable isoform of HuR that, when overexpressed, maintains its association with pp32/PHAP-I and delays the apoptotic response. Thus, we propose a model in which HuR association with pp32/PHAP-I and its caspase-mediated cleavage constitutes a regulatory step that contributes to an amplified apoptotic response.

R. Mazroui's present address is Unite de Recherche en Genetique Humaine et Moleculaire, Centre de Recherche Hopital Saint-Francois d'Assise, Universite Laval, Quebec City, Quebec G1L 3L5, Canada.

Abbreviations used in this paper: AMC, 7-amino-4-methylcoumarin; CP, cleavage product; cyt c, cytochrome c; HNS, HuR nucleocytoplasmic shuttling; HS, heat shock; PARP, poly(ADP-ribose) polymerase; PI, propidium iodide; RRM, RNA recognition motif; STS, staurosporine; wt, wild type.


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