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First published online 24 February 2009
doi: 10.1242/jcs.050013

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Huntingtin promotes cell survival by preventing Pak2 cleavage

Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK

^* Author for correspondence (e-mail: dcr1000{at}hermes.cam.ac.uk)

Accepted 20 November 2008

Huntington's disease is caused by a polyglutamine expansion in the huntingtin protein. Wild-type huntingtin, by contrast, appears to protect cells from pro-apoptotic insults. Here we describe a novel anti-apoptotic function for huntingtin. When cells are exposed to Fas-related signals, the ubiquitously expressed p21-activated kinase 2 (Pak2) can be activated via cleavage by caspases to release a constitutively active C-terminal fragment, which mediates cell death. Our data show that huntingtin interacts with Pak2. Overexpression of huntingtin significantly inhibits caspase-3-mediated and caspase-8-mediated cleavage of Pak2 in cells. Moreover, huntingtin prevents Pak2 cleavage by caspase-3 and caspase-8 in vitro. Although huntingtin is cytoprotective in wild-type cells that are exposed to TNF, it has no significant benefit in TNF-treated cells with Pak2 knockdown. Thus, huntingtin exerts anti-apoptotic effects by binding to Pak2, which reduces the abilities of caspase-3 and caspase-8 to cleave Pak2 and convert it into a mediator of cell death.

Key words: Huntingtin, Caspase, Pak2, TNF

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