Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2.
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 gamma-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 gamma-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.
Wang
Hua-Qin
HQ
Neurology Unit, Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga, Japan.
Nakaya
Yoshifumi
Y
Du
Zhenyu
Z
Yamane
Takuya
T
Shirane
Michiko
M
Kudo
Takashi
T
Takeda
Masatoshi
M
Takebayashi
Koichi
K
Noda
Yoichi
Y
Nakayama
Keiichi I
KI
Nishimura
Masaki
M
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1; D053766:Presenilin-2; D011485:Protein Binding / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
C471205:FKBP8 protein, human; C119437:Fkbp8 protein, mouse; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D019253:Proto-Oncogene Proteins c-bcl-2; C095101:Psen2 protein, mouse; D022021:Tacrolimus Binding Proteins