Human Molecular Genetics Advance Access originally published online on May 19, 2005
Human Molecular Genetics 2005 14(13):1889-1902; doi:10.1093/hmg/ddi195
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Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2
1Neurology Unit, Molecular Neuroscience Research Center and 2Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta-Tsukinowacho, Otsu, Shiga 520-2192, Japan, 3Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan and 4Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
* To whom correspondence should be addressed. Tel: +81 775482327; Fax: +81 775482402; Email: mnishimu{at}belle.shiga-med.ac.jp
Received April 18, 2005; Accepted May 12, 2005
Presenilins 1 and 2 (PS1/2), causative molecules for familial Alzheimer's disease (FAD), are multipass transmembrane proteins localized predominantly in the endoplasmic reticulum (ER) and Golgi apparatus. Heteromeric protein complexes containing PS1/2 are thought to participate in several functions, including intramembrane proteolysis mediated by their 
-secretase activities. Previous studies have shown that PS1/2 are also involved in the regulation of apoptotic cell death, although the underlying mechanism remains unknown. Here, we demonstrate that FKBP38, an immunophilin family member residing in the mitochondrial membrane, is an authentic PS1/2-interacting protein. PS1/2 and FKBP38 form macromolecular complexes together with anti-apoptotic Bcl-2. PS1/2 promote the degradation of FKBP38 and Bcl-2 and sequester these proteins in the ER/Golgi compartments, thereby inhibiting FKBP38-mediated mitochondrial targeting of Bcl-2 via a -secretase-independent mechanism. Thus, PS1/2 increase the susceptibility to apoptosis by antagonizing the anti-apoptotic function of FKBP38. In contrast, C-terminal fragments of caspase-processed PS1/2 redistribute Bcl-2 to the mitochondria by abrogating the activity of full-length PS1/2, resulting in a dominant-negative anti-apoptotic effect. In cultured cells and mutant PS1-knockin mice brains, FAD-linked PS1/2 mutants enhance the pro-apoptotic activity by causing a more efficient reduction in mitochondrial Bcl-2 than wild-type PS1/2. These results suggest a novel molecular mechanism for the regulation of mitochondria-mediated apoptosis by competition between PS1/2 and FKBP38 for subcellular targeting of Bcl-2. Excessive pro-apoptotic activity of PS1/2 may play a role in the pathogenesis of FAD.
Present address: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.
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