Proapoptotic Mitochondrial Carrier Homolog Protein PSAP Mediates Death Receptor 6 Induced Apoptosis

Article type: Research Article

Authors: Zhang, Jingtian^a | Zhao, Zhizhuang Joe^{a; d} | Fu, Xueqi^a | Niu, Han^a | Hu, Chen^e | Dong, Yunzhou^f | Cui, Mei-Zhen^c | Zhang, Fuqiang^b | Zeng, Linlin^{a; *} | Xu, Xuemin^{c; *}

Affiliations: [a] Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun, China | [b] Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, China | [c] Department of Biology, College of Arts and Sciences, University of Texas of the Permian Basin, Odessa, TX, USA | [d] Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA | [e] School of Life Sciences and Technology, Tongji University, Shanghai, China | [f] Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Linlin Zeng, Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun 130012, China. E-mail: zenglinlin@jlu.edu.cn. and Xuemin Xu, Department of Biology, College of Arts and Sciences, University of Texas of the Permian Basin, Odessa, TX 79762, USA. Tel.: +1 432 552 2271; Fax: +1 432 552 3230; E-mail: xu_x@utpb.edu.

Abstract: Presenilin-associated protein (PSAP) was originally identified as a mitochondrial proapoptotic protein. To further explore the apoptotic pathway that involves PSAP, our yeast two-hybrid screen revealed that PSAP interacts with a death receptor, DR6. DR6 is a relatively less common member of the death receptor family and has been shown to mediate the neurotoxicity of amyloid-β, mutant SOD1, and prion proteins and has also been implicated in the regulation of immune cell proliferation and differentiation. Our previous study showed that DR6 induces apoptosis via a unique mitochondria-dependent pathway different from the conventional death receptor-mediated extrinsic apoptotic pathways. Thus, the interaction of DR6 with PSAP established a direct molecular link between DR6 and mitochondrial apoptotic pathway. We investigated the possible role of PSAP in DR6-induced apoptosis. Interestingly, it was discovered that knockdown of PSAP strongly inhibited DR6-induced apoptosis. To further elucidate the mechanism by which PSAP mediates DR6-induced mitochondria-dependent apoptosis, our data demonstrated that knockdown of PSAP blocked DR6-induced Bax translocation and cytochrome c release from the mitochondria. Moreover, it was found that both PSAP and DR6 form complexes with Bax, but at different subcellular locations. The DR6-Bax complex was detected in the cytosolic fraction while the PSAP-Bax complex was detected in the mitochondrial fraction. The observation that knockdown of DR6 significantly reduced the amount of PSAP-Bax complex detected in mitochondria suggests a possibility that DR6-bound Bax is transferred to PSAP upon interaction with PSAP at the mitochondria, leading to cytochrome c release and eventually apoptosis.

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, apoptosis, DR6, mitochondria, neurodegenerative disease, PSAP

DOI: 10.3233/JAD-191086

Journal: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1097-1106, 2020