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 TNFα, it has no significant benefit in TNFα-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.
We thank Rolf Jakobi for Myc-Pak2, GFP-Pak2 and GFP-Pak2p34 constructs, and Marcy Macdonald for Htt–/– ES cells. We are grateful to the MRC and the Wellcome Trust (Senior Clinical Fellowship) for funding to D.C.R. and his group. Deposited in PMC for release after 6 months.
