EMBO Molecular Medicine (Jul 2022)

Sigma‐1 receptor attenuates osteoclastogenesis by promoting ER‐associated degradation of SERCA2

  • Xiaoan Wei,
  • Zeyu Zheng,
  • Zhenhua Feng,
  • Lin Zheng,
  • Siyue Tao,
  • Bingjie Zheng,
  • Bao Huang,
  • Xuyang Zhang,
  • Junhui Liu,
  • Yilei Chen,
  • Wentian Zong,
  • Zhi Shan,
  • Shunwu Fan,
  • Jian Chen,
  • Fengdong Zhao

DOI
https://doi.org/10.15252/emmm.202115373
Journal volume & issue
Vol. 14, no. 7
pp. n/a – n/a

Abstract

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Abstract Sigma‐1 receptor (Sigmar1) is a specific chaperone located in the mitochondria‐associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model. In contrast, overexpression of Sigmar1 locally alleviated the osteoporosis phenotype. Treatment with Sigmar1 agonists impaired both human and mice osteoclast formation in vitro. Mechanistically, SERCA2 was identified to interact with Sigmar1 based on the immunoprecipitation‐mass spectrum (IP‐MS) and co‐immunoprecipitation (co‐IP) assays, and Q615 of SERCA2 was confirmed to be the critical residue for their binding. Furthermore, Sigmar1 promoted SERCA2 degradation through Hrd1/Sel1L‐dependent ER‐associated degradation (ERAD). Ubiquitination of SERCA2 at K460 and K541 was responsible for its proteasomal degradation. Consequently, inhibition of SERCA2 impeded Sigmar1 deficiency enhanced osteoclastogenesis. Moreover, we found that dimemorfan, an FDA‐approved Sigmar1 agonist, effectively rescued bone mass in various established bone‐loss models. In conclusion, Sigmar1 is a negative regulator of osteoclastogenesis, and activation of Sigmar1 by dimemorfan may be a potential treatment for osteoporosis in clinical practice.

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