Abstract
Site-1 protease (S1P) is a Golgi-located protein that activates unique membrane-bound latent transcription factors, and it plays an indispensable role in endoplasmic reticulum stress, lipid metabolism, inflammatory response and lysosome function. A patient with S1P mutation exhibits severe skeletal dysplasia with kyphoscoliosis, dysmorphic facial features and pectus carinatum. However, whether S1P regulates bone remodeling by affecting osteoclastogenesis remains elusive. Here, we show that S1P is indeed a positive regulator of osteoclastogenesis. S1P ablation in mice led to significant osteosclerosis compared with wild-type littermates. Mechanistically, S1P showed upregulated during osteoclastogenesis and was identified as a direct target of miR-9-5p. S1P deletion in bone marrow monocytes (BMMs) inhibited ATF6 and SREBP2 maturation, which subsequently impeded CHOP/SREBP2-complex-induced LC3 expression and autophagy flux. Consistently, transfection of LC3 adenovirus evidently rescued osteoclastogenesis in S1P-deficient BMMs. We then identified the interaction regions between CHOP and SREBP2 by Co-immunoprecipitation (Co-IP) and molecular docking. Furthermore, S1P deletion or inhibitor efficaciously rescued ovariectomized (OVX)- and LPS-induced bone loss in vivo. Collectively, we showed that S1P regulates osteoclast differentiation in a LC3 dependent manner and so is a potential therapy target for osteoporosis.
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Change history
06 January 2026
The original online version of this article was revised: During image editing, layer overlap resulted in two completely identical images appearing in Fig. 8C. We assure you that this is merely an editing error with the images and replacing the images will not affect the conclusions of the paper.
24 February 2026
A Correction to this paper has been published: https://doi.org/10.1038/s41418-025-01659-5
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Acknowledgements
We thank Prof. Di Wang for providing S1P flox/flox mice. We thank Dr. An Qin for assistant on the project. We thank M.S. Daojiong Wang for assistance with molecular docking. We also thank Dr. Shishi Li and M.S. Yier Zhou for assistance with confocal microscopy work. We also thank Prof. M.A. Adams and Prof. P. Dolan for polishing the manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (81902231, 81871796, 81802192, 81802188), Zhejiang Provincial Natural Science Foundation of China (LQ19H060005).
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ZZ, XZ, BH, JL, XW, and ZS performed the experiments, analyzed the data and edited the manuscript. HW, ZF, and YC performed mice experiments and revised the manuscript. SF conceived the project and revised the manuscript. FZ and JC conceived the project, designed the experiments and edited the manuscript. All authors discussed the results and contributed to the preparation of the manuscript.
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The original online version of this article was revised: During image editing, layer overlap resulted in two completely identical images appearing in Fig. 8C. We assure you that this is merely an editing error with the images and replacing the images will not affect the conclusions of the paper.
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Zheng, Z., Zhang, X., Huang, B. et al. Site-1 protease controls osteoclastogenesis by mediating LC3 transcription. Cell Death Differ 28, 2001–2018 (2021). https://doi.org/10.1038/s41418-020-00731-6
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DOI: https://doi.org/10.1038/s41418-020-00731-6
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