title: Acyl-CoA Dehydrogenase Drives Heat Adaptation by Sequestering Fatty Acids.
abstract: Cells adapt to temperature shifts by adjusting levels of lipid desaturation and membrane fluidity. This fundamental process occurs in nearly all forms of life, but its mechanism in eukaryotes is unknown. We discovered that the evolutionarily conserved Caenorhabditis elegans gene acdh-11 (acyl-CoA dehydrogenase [ACDH]) facilitates heat adaptation by regulating the lipid desaturase FAT-7. Human ACDH deficiency causes the most common inherited disorders of fatty acid oxidation, with syndromes that are exacerbated by hyperthermia. Heat upregulates acdh-11 expression to decrease fat-7 expression. We solved the high-resolution crystal structure of ACDH-11 and established the molecular basis of its selective and high-affinity binding to C11/C12-chain fatty acids. ACDH-11 sequesters C11/C12-chain fatty acids and prevents these fatty acids from activating nuclear hormone receptors and driving fat-7 expression. Thus, the ACDH-11 pathway drives heat adaptation by linking temperature shifts to regulation of lipid desaturase levels and membrane fluidity via an unprecedented mode of fatty acid signaling.
authors.affiliation: Department of Biology, Howard Hughes Medical Institute, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: dengke.ma@ucsf.edu.
authors.forename: Dengke K
authors.initials: DK
authors.lastname: Ma
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biology, Howard Hughes Medical Institute, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Alice Y
authors.initials: AY
authors.lastname: Lu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Sun
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sidi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Lipidomix GmbH, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.affiliation: Department of Biology, Freshwater and Stress Ecology, Humboldt-Universität zu Berlin, Spaethstrasse 80/81, 12437 Berlin, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Menzel
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Biology, Howard Hughes Medical Institute, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: horvitz@mit.edu.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006358:Hot Temperature; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment
chemical_list: D029742:Caenorhabditis elegans Proteins; D005227:Fatty Acids; C000599816:11 acyl-CoA dehydrogenase, C elegans; D042964:Acyl-CoA Dehydrogenase