Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD

被引:47
作者
Escudero, Silvia [1 ,2 ]
Zaganjor, Elma [3 ]
Lee, Susan [1 ,2 ]
Mill, Christopher P. [4 ]
Morgan, Ann M. [1 ,2 ]
Crawford, Emily B. [1 ,2 ]
Chen, Jiahao [5 ,6 ]
Wales, Thomas E. [7 ]
Mourtada, Rida [1 ,2 ]
Luccarelli, James [1 ,2 ]
Bird, Gregory H. [1 ,2 ]
Steidl, Ulrich [5 ,6 ]
Engen, John R. [7 ]
Haigis, Marcia C. [3 ]
Opferman, Joseph T. [4 ]
Walensky, Loren D. [1 ,2 ]
机构
[1] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA
[2] Dana Farber Canc Inst, Linde Program Canc Chem Biol, Boston, MA 02215 USA
[3] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA
[4] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale, Memphis, TN 38105 USA
[5] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
[6] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA
[7] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA
基金
美国国家科学基金会; 加拿大健康研究院;
关键词
EXCHANGE-MASS-SPECTROMETRY; ANTI-APOPTOTIC MCL-1; DEHYDROGENASE-DEFICIENCY; PROTEIN; CELLS; BCL-2; EXPRESSION; INHIBITOR; DEATH; BAX;
D O I
10.1016/j.molcel.2018.02.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) alpha helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid beta-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1(Matrix)) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1(Matrix) alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 alpha helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.
引用
收藏
页码:729 / +
页数:22
相关论文
共 59 条
[1]   Redefining the BH3 Death Domain as a 'Short Linear Motif' [J].
Aouacheria, Abdel ;
Combet, Christophe ;
Tompa, Peter ;
Hardwick, J. Marie .
TRENDS IN BIOCHEMICAL SCIENCES, 2015, 40 (12) :736-748
[2]   Mechanisms and Dynamics of Protein Acetylation in Mitochondria [J].
Baeza, Josue ;
Smallegan, Michael J. ;
Denu, John M. .
TRENDS IN BIOCHEMICAL SCIENCES, 2016, 41 (03) :231-244
[3]   Inhibition of Pro-Apoptotic BAX by a Noncanonical Interaction Mechanism [J].
Barclay, Lauren A. ;
Wales, Thomas E. ;
Garner, Thomas P. ;
Wachter, Franziska ;
Lee, Susan ;
Guerra, Rachel M. ;
Stewart, Michelle L. ;
Braun, Craig R. ;
Bird, Gregory H. ;
Gavathiotis, Evripidis ;
Engen, John R. ;
Walensky, Loren D. .
MOLECULAR CELL, 2015, 57 (05) :873-886
[4]   The landscape of somatic copy-number alteration across human cancers [J].
Beroukhim, Rameen ;
Mermel, Craig H. ;
Porter, Dale ;
Wei, Guo ;
Raychaudhuri, Soumya ;
Donovan, Jerry ;
Barretina, Jordi ;
Boehm, Jesse S. ;
Dobson, Jennifer ;
Urashima, Mitsuyoshi ;
Mc Henry, Kevin T. ;
Pinchback, Reid M. ;
Ligon, Azra H. ;
Cho, Yoon-Jae ;
Haery, Leila ;
Greulich, Heidi ;
Reich, Michael ;
Winckler, Wendy ;
Lawrence, Michael S. ;
Weir, Barbara A. ;
Tanaka, Kumiko E. ;
Chiang, Derek Y. ;
Bass, Adam J. ;
Loo, Alice ;
Hoffman, Carter ;
Prensner, John ;
Liefeld, Ted ;
Gao, Qing ;
Yecies, Derek ;
Signoretti, Sabina ;
Maher, Elizabeth ;
Kaye, Frederic J. ;
Sasaki, Hidefumi ;
Tepper, Joel E. ;
Fletcher, Jonathan A. ;
Tabernero, Josep ;
Baselga, Jose ;
Tsao, Ming-Sound ;
Demichelis, Francesca ;
Rubin, Mark A. ;
Janne, Pasi A. ;
Daly, Mark J. ;
Nucera, Carmelo ;
Levine, Ross L. ;
Ebert, Benjamin L. ;
Gabriel, Stacey ;
Rustgi, Anil K. ;
Antonescu, Cristina R. ;
Ladanyi, Marc ;
Letai, Anthony .
NATURE, 2010, 463 (7283) :899-905
[5]  
Bird Gregory H, 2011, Curr Protoc Chem Biol, V3, P99, DOI 10.1002/9780470559277.ch110042
[6]   Photoreactive Stapled BH3 Peptides to Dissect the BCL-2 Family Interactome [J].
Braun, Craig R. ;
Mintseris, Julian ;
Gavathiotis, Evripidis ;
Bird, Gregory H. ;
Gygi, Steven P. ;
Walensky, Loren D. .
CHEMISTRY & BIOLOGY, 2010, 17 (12) :1325-1333
[7]   Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B Cell Lymphoma [J].
Caro, Pilar ;
Kishan, Amar U. ;
Norberg, Erik ;
Stanley, Illana A. ;
Chapuy, Bjoern ;
Ficarro, Scott B. ;
Polak, Klaudia ;
Tondera, Daniel ;
Gounarides, John ;
Yin, Hong ;
Zhou, Feng ;
Green, Michael R. ;
Chen, Linfeng ;
Monti, Stefano ;
Marto, Jarrod A. ;
Shipp, Margaret A. ;
Danial, Nika N. .
CANCER CELL, 2012, 22 (04) :547-560
[8]   Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members [J].
Certo, Michael ;
Moore, Victoria Del Gaizo ;
Nishino, Mari ;
Wei, Guo ;
Korsmeyer, Stanley ;
Armstrong, Scott A. ;
Letai, Anthony .
CANCER CELL, 2006, 9 (05) :351-365
[9]   Characterization of L-aminocarnitine, an inhibitor of fatty acid oxidation [J].
Chegary, Malika ;
Brinke, Heleen te ;
Doolaard, Mirjam ;
Ijlst, Lodewijk ;
Wijburg, Frits A. ;
Wanders, Ronald J. A. ;
Houten, Sander M. .
MOLECULAR GENETICS AND METABOLISM, 2008, 93 (04) :403-410
[10]   BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis [J].
Cheng, EHYA ;
Wei, MC ;
Weiler, S ;
Flavell, RA ;
Mak, TW ;
Lindsten, T ;
Korsmeyer, SJ .
MOLECULAR CELL, 2001, 8 (03) :705-711