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Sex specificity of the C. elegans metabolome

ABSTRACT: Sex specificity of the C. elegans metabolome Russell N. Burkhardt1, Alexander B. Artyukhin1,3, Erin Z. Aprison2, Brian J. Curtis1, Bennett W. Fox1, Andreas H. Ludewig1, Amaresh Chaturbedi4, Oishika Panda1, Chester J. J. Wrobel1, Siu S. Lee4, Ilya Ruvinsky2, and Frank C. Schroeder1, 1Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States 2Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, United States 3Current address: Chemistry Department, College of Environmental Science and Forestry, State University of New York, Syracuse, New York 13210, United States 4Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, United States Correspondence to fs31@cornell.edu

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Caenorhabditis Briggsae (ncbitaxon:6238) Caenorhabditis Elegans (ncbitaxon:6239)

SUBMITTER: Frank Schroeder

PROVIDER: MSV000089965 | MassIVE | Mon Jul 25 07:26:00 BST 2022

REPOSITORIES: MassIVE

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Project description:Germanos M1*. Yau B1*. Taper M1. An Y1. Yeoman C1. Wilson A1. Cattin-Ortolá J2. Maslar D3. Tong J1. Naghiloo S1. Needham E4. Diaz-Vegas A4. Larance M1. Thomas H5. Seidah NG6. von Blume J7. James DE4. Thorn P1. Ailion M2. Asensio C3. Kebede MA1. 1 School of Medical Sciences, Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia. 2 Department of Biochemistry, University of Washington, Seattle, WA USA. 3 Department of Biological Sciences, University of Denver, Denver, Colorado 80210, United States. 4 Discipline of Biochemistry and Molecular Biology, School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia. 5 Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Melbourne, Victoria, Australia. 6 Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada. 7 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.. *These authors contributed equally. Abstract Here we investigate the role of Cab45 in β-cell function and insulin secretory granule (ISG) biogenesis. Cab45 has been known as a ubiquitously expressed, soluble, trans-Golgi network (TGN) resident protein. We demonstrate its expression in pancreatic islets but not exocrine tissue, and localization in both Golgi and granular/vesicular compartments of primary β-cells. In INS1 cells, Cab45 is held in the cis-Golgi by a calcium-dependent mechanism but is capable of anterograde trafficking beyond the TGN. ISG biogenesis is maintained in Cab45 knockout INS1 cells which exhibit insulin hypersecretion due to dysregulated calcium homeostasis, leading to ISG depletion that is reinstated by rest at low glucose or Cab45 overexpression. Overexpressed Cab45 traffics directly into ISGs and increases biogenesis. Expression of a Cab45 variant that cannot bind calcium drives superior ISG rescue and has reduced ISG residency. In humans, anterograde Cab45 trafficking increases with worsening obesity, suggesting recruitment to drive cargo transit and support secretory output. Humans with type 2 diabetes, however, contain a greater proportion of Cab45-occupied ISGs and a loss of Golgi-localized Cab45 compared to non-diabetics. These insights position Cab45 as an exciting candidate for further investigation into mechanisms associated with β-cell compensation and failure.

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Sex specificity of the C. elegans metabolome

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