Protein palmitoylation-mediated palmitic acid sensing causes blood-testis barrier damage via inducing ER stress
Xie Ge,
Zhaowanyue He,
Chun Cao,
Tongmin Xue,
Jun Jing,
Rujun Ma,
Wei Zhao,
Ling Liu,
Kadiliya Jueraitetibaike,
Jinzhao Ma,
Yuming Feng,
Zhang Qian,
Zhichuan Zou,
Li Chen,
Chuanhai Fu,
Ninghong Song,
Bing Yao
Affiliations
Xie Ge
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Zhaowanyue He
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Chun Cao
The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
Tongmin Xue
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
Jun Jing
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Rujun Ma
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Wei Zhao
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Ling Liu
CAS Center for Excellence in Molecular Cell Sciences, Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China
Kadiliya Jueraitetibaike
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Jinzhao Ma
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Yuming Feng
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China; The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
Zhang Qian
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Zhichuan Zou
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Li Chen
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China
Chuanhai Fu
CAS Center for Excellence in Molecular Cell Sciences, Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China; Corresponding author.;
Ninghong Song
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, China; Corresponding author.;
Bing Yao
Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 210029, Jiangsu, China; Corresponding author. Department of Reproductive Medical Center, Jinling Hospital, Nanjing University, School of Medicine, Nanjing, 210002, Jiangsu, China.
Blood-testis barrier (BTB) damage promotes spermatogenesis dysfunction, which is a critical cause of male infertility. Dyslipidemia has been correlated with male infertility, but the major hazardous lipid and the underlying mechanism remains unclear. In this study, we firstly discovered an elevation of palmitic acid (PA) and a decrease of inhibin B in patients with severe dyszoospermia, which leaded us to explore the effects of PA on Sertoli cells. We observed a damage of BTB by PA. PA penetration to endoplasmic reticulum (ER) and its damage to ER structures were exhibited by microimaging and dynamic observation, and consequent ER stress was proved to mediate PA-induced Sertoli cell barrier disruption. Remarkably, we demonstrated a critical role of aberrant protein palmitoylation in PA-induced Sertoli cell barrier dysfunction. An ER protein, Calnexin, was screened out and was demonstrated to participate in this process, and suppression of its palmitoylation showed an ameliorating effect. We also found that ω-3 poly-unsaturated fatty acids down-regulated Calnexin palmitoylation, and alleviated BTB dysfunction. Our results indicate that dysregulated palmitoylation induced by PA plays a pivotal role in BTB disruption and subsequent spermatogenesis dysfunction, suggesting that protein palmitoylation might be therapeutically targetable in male infertility.
