MOAP-1 Mediates Fas-Induced Apoptosis in Liver by Facilitating tBid Recruitment to Mitochondria.
Fas apoptotic signaling regulates diverse physiological processes. Acute activation of Fas signaling triggers massive apoptosis in liver. Upon Fas receptor stimulation, the BH3-only protein Bid is cleaved into the active form, tBid. Subsequent tBid recruitment to mitochondria, which is facilitated by its receptor MTCH2 at the outer mitochondrial membrane (OMM), is a critical step for commitment to apoptosis via the effector proteins Bax or Bak. MOAP-1 is a Bax-binding protein enriched at the OMM. Here, we show that MOAP-1-deficient mice are resistant to Fas-induced hepatocellular apoptosis and lethality. In the absence of MOAP-1, mitochondrial accumulation of tBid is markedly impaired. MOAP-1 binds to MTCH2, and this interaction appears necessary for MTCH2 to engage tBid. These findings reveal a role for MOAP-1 in Fas signaling in the liver by promoting MTCH2-mediated tBid recruitment to mitochondria.
Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore.
Chong Teik
CT
Tan
Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore; School of Life Sciences, Xiamen University, Xiamen 361102, China.
Qi-Ling
QL
Zhou
Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore.
Yu-Chin
YC
Su
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore.
Nai Yang
NY
Fu
Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore.
Hao-Chun
HC
Chang
Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore.
Ran N
RN
Tao
Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore.
Sunil K
SK
Sukumaran
Division of iHOPE, Department of Pediatrics, Faculty of Medicine and Dentistry, Women and Children's Research Institute and Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2N8, Canada.
Shairaz
S
Baksh
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.
Yee-Joo
YJ
Tan
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore; Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
Kanaga
K
Sabapathy
School of Life Sciences, Xiamen University, Xiamen 361102, China.
Chun-Dong
CD
Yu
Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore. Electronic address: phayuv@nus.edu.sg.
Victor C
VC
Yu
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D045325:HCT116 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D011485:Protein Binding; D019014:fas Receptor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C491899:Fas protein, mouse; C428449:MOAP1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; C492394:Moap1 protein, mouse; C550380:Mtch2 protein, mouse; D019014:fas Receptor