Hepatic palmitoyl-proteomes and acyl-protein thioesterase protein proximity networks link lipid modification and mitochondria
Sarah L. Speck,
Dhaval P. Bhatt,
Qiang Zhang,
Sangeeta Adak,
Li Yin,
Guifang Dong,
Chu Feng,
Wei Zhang,
M. Ben Major,
Xiaochao Wei,
Clay F. Semenkovich
Affiliations
Sarah L. Speck
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA
Dhaval P. Bhatt
Department of Cell Biology & Physiology, Washington University, St. Louis, MO 63110, USA
Qiang Zhang
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA
Sangeeta Adak
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA
Li Yin
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA
Guifang Dong
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA; Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
Chu Feng
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA
Wei Zhang
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA
M. Ben Major
Department of Cell Biology & Physiology, Washington University, St. Louis, MO 63110, USA; Department of Otolaryngology, Washington University, St. Louis, MO 63110, USA
Xiaochao Wei
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA; Corresponding author
Clay F. Semenkovich
Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis, MO 63110, USA; Department of Cell Biology & Physiology, Washington University, St. Louis, MO 63110, USA; Corresponding author
Summary: Acyl-protein thioesterases 1 and 2 (APT1 and APT2) reverse S-acylation, a potential regulator of systemic glucose metabolism in mammals. Palmitoylation proteomics in liver-specific knockout mice shows that APT1 predominates over APT2, primarily depalmitoylating mitochondrial proteins, including proteins linked to glutamine metabolism. miniTurbo-facilitated determination of the protein-protein proximity network of APT1 and APT2 in HepG2 cells reveals APT proximity networks encompassing mitochondrial proteins including the major translocases Tomm20 and Timm44. APT1 also interacts with Slc1a5 (ASCT2), the only glutamine transporter known to localize to mitochondria. High-fat-diet-fed male mice with dual (but not single) hepatic deletion of APT1 and APT2 have insulin resistance, fasting hyperglycemia, increased glutamine-driven gluconeogenesis, and decreased liver mass. These data suggest that APT1 and APT2 regulation of hepatic glucose metabolism and insulin signaling is functionally redundant. Identification of substrates and protein-protein proximity networks for APT1 and APT2 establishes a framework for defining mechanisms underlying metabolic disease.