Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake

Song-Hua Hu; Xia-Di He; Ji Nie; Jun-Li Hou; Jiang Wu; Xiao-Yan Liu; Yun Wei; Hui-Ru Tang; Wen-Xing Sun; Shu-Xian Zhou; Yi-Yuan Yuan; Yan-Peng An; Guo-Quan Yan; Yan Lin; Peng-Cheng Lin; Jean J Zhao; Ming-Liang Ye; Jian-Yuan Zhao; Wei Xu; Shi-Min Zhao

doi:10.1016/j.celrep.2022.110509

Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake

Cell Rep. 2022 Mar 15;38(11):110509. doi: 10.1016/j.celrep.2022.110509.

Authors

Song-Hua Hu¹, Xia-Di He¹, Ji Nie¹, Jun-Li Hou², Jiang Wu³, Xiao-Yan Liu⁴, Yun Wei¹, Hui-Ru Tang⁵, Wen-Xing Sun¹, Shu-Xian Zhou¹, Yi-Yuan Yuan¹, Yan-Peng An⁵, Guo-Quan Yan⁵, Yan Lin¹, Peng-Cheng Lin⁶, Jean J Zhao⁷, Ming-Liang Ye⁸, Jian-Yuan Zhao⁹, Wei Xu¹⁰, Shi-Min Zhao¹¹

Affiliations

¹ Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, P.R. China; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Medical Epigenetics, and Children's Hospital of Fudan University, Shanghai 200438, P.R. China.
² Department of Chemistry, Fudan University, Shanghai 200438, P.R. China.
³ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230027, P. R. China.
⁴ CAS Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China.
⁵ Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, P.R. China.
⁶ Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining 810007, P. R. China.
⁷ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁸ CAS Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China. Electronic address: mingliang@dicp.ac.cn.
⁹ Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, P.R. China; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Medical Epigenetics, and Children's Hospital of Fudan University, Shanghai 200438, P.R. China. Electronic address: zhaojy@fudan.edu.cn.
¹⁰ Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, P.R. China; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Medical Epigenetics, and Children's Hospital of Fudan University, Shanghai 200438, P.R. China. Electronic address: xuwei_0706@fudan.edu.cn.
¹¹ Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Shanghai 200438, P.R. China; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Medical Epigenetics, and Children's Hospital of Fudan University, Shanghai 200438, P.R. China; Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining 810007, P. R. China. Electronic address: zhaosm@fudan.edu.cn.

Abstract

Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.

Keywords: Akt signaling; DHA/EPA; fatty acylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acylation
Animals
Docosahexaenoic Acids / metabolism
Docosahexaenoic Acids / pharmacology
Eicosapentaenoic Acid / metabolism
Eicosapentaenoic Acid / pharmacology
Fatty Acids, Unsaturated
Glucose / metabolism
Mice
Phosphatidylinositol 3-Kinases* / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Tryptophan* / metabolism

Substances

Fatty Acids, Unsaturated
Docosahexaenoic Acids
Tryptophan
Eicosapentaenoic Acid
Proto-Oncogene Proteins c-akt
Glucose

Grants and funding

R35 CA210057/CA/NCI NIH HHS/United States