Human nuclear clusterin mediates apoptosis by interacting with Bcl‐XL through C‐terminal coiled coil domain

Abstract Clusterin (CLU), a glycoprotein, is involved in apoptosis, producing two alternatively spliced isoforms in various cell types. The pro‐apoptotic CLU appears to be a nuclear isoform (nuclear clusterin; nCLU), and the secretory CLU (sCLU) is thought to be anti‐apoptotic. The detailed molecular mechanism of nCLU as a pro‐apoptotic molecule has not yet been clear. In the current study, overexpressed nCLU induced apoptosis in human kidney cells. Biochemical studies revealed that nCLU sequestered Bcl‐XL via a putative BH3 motif in the C‐terminal coiled coil (CC2) domain, releasing Bax, and promoted apoptosis accompanied by activation of caspase‐3 and cytochrome c release. These results suggest a novel mechanism of apoptosis mediated by nCLU as a pro‐apoptotic molecule. J. Cell. Physiol. 227: 1157–1167, 2012. © 2011 Wiley Periodicals, Inc.