PPT1 regulation of HSP90α depalmitoylation participates in the pathogenesis of hyperandrogenism

Tongmin Xue; Shanmeizi Zhao; Hong Zhang; Ting Tang; Lu Zheng; Jun Jing; Xie Ge; Rujun Ma; Jinzhao Ma; Xiaoyan Ren; Kadiliya Jueraitetibaike; Zhigang Guo; Li Chen; Bing Yao

doi:10.1016/j.isci.2023.106131

PPT1 regulation of HSP90α depalmitoylation participates in the pathogenesis of hyperandrogenism

iScience. 2023 Feb 3;26(3):106131. doi: 10.1016/j.isci.2023.106131. eCollection 2023 Mar 17.

Authors

Tongmin Xue^{1

2

3}, Shanmeizi Zhao^{4

5}, Hong Zhang⁵, Ting Tang⁵, Lu Zheng⁵, Jun Jing^{1

5

2}, Xie Ge⁵, Rujun Ma⁵, Jinzhao Ma⁵, Xiaoyan Ren⁴, Kadiliya Jueraitetibaike⁵, Zhigang Guo⁴, Li Chen^{1

4

5

2}, Bing Yao^{1

4

5

2}

Affiliations

¹ Reproductive Medical Center, Jinling Hospital Department, Nanjing Medical University, Nanjing, Jiangsu 210002, China.
² State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211116, China.
³ Reproductive Medical Center, Clinical Medical College (Northern Jiangsu People's Hospital), Yangzhou University, Yangzhou, Jiangsu 225001, China.
⁴ Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, China.
⁵ Center of Reproductive Medicine, Nanjing Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu 210002, China.

Abstract

Ovarian granulosa cells (GCs) in the follicle are the important mediator of steroidogenesis and foster oocyte maturation. Evidences suggested that the function of GCs could be regulated by S-palmitoylation. However, the role of S-palmitoylation of GCs in ovarian hyperandrogenism remains elusive. Here, we demonstrated that the protein from GCs in ovarian hyperandrogenism phenotype mouse group exhibits lower palmitoylation level compared with that in the control group. Using S-palmitoylation-enriched quantitative proteomics, we identified heat shock protein isoform α (HSP90α) with lower S-palmitoylation levels in ovarian hyperandrogenism phenotype group. Mechanistically, S-palmitoylation of HSP90α modulates the conversion of androgen to estrogens via the androgen receptor (AR) signalling pathway, and its level is regulated by PPT1. Targeting AR signaling by using dipyridamole attenuated ovarian hyperandrogenism symptoms. Our data help elucidate ovarian hyperandrogenism from perspective of protein modification and provide new evidence showing that HSP90α S-palmitoylation modification might be a potential pharmacological target for ovarian hyperandrogenism treatment.

Keywords: Health sciences; Molecular biology; Proteomics.