Site-1 protease controls osteoclastogenesis by mediating LC3 transcription

• Published in: Cell death and differentiation 2021-06, Vol.28 (6), p.2001-2018
• Main Authors: Zheng, Zeyu, Zhang, Xuyang, Huang, Bao, Liu, Junhui, Wei, Xiaoan, Shan, Zhi, Wu, Hao, Feng, Zhenhua, Chen, Yilei, Fan, Shunwu, Zhao, Fengdong, Chen, Jian
• Format: Article
• Language: English
• Subjects: 13/51; 13/95; 14/19; 38/109; 38/77; 42/89; 45/15; 631/443; 631/80/39/2345; 64/110; 96/31; 96/35; Adenoviruses; Animals; Apoptosis; Arthritis; Autophagy; Biochemistry; Biomedical and Life Sciences; Bone dysplasia; Bone loss; Bone marrow; Bone remodeling; Cell Biology; Cell Cycle Analysis; Cell Differentiation; Endoplasmic reticulum; Golgi apparatus; Humans; Immunoprecipitation; Inflammation; Kinases; Kyphosis; Life Sciences; Lipid metabolism; Lipopolysaccharides; Membrane proteins; Mice; Microtubule-Associated Proteins - metabolism; Monocytes; Osteoarthritis; Osteoclastogenesis; Osteoclasts - metabolism; Osteoporosis; Osteosclerosis; Ovariectomy; Phagocytosis; Proprotein Convertases - metabolism; Protein expression; Proteinase; Proteins; Scoliosis; Serine Endopeptidases - metabolism; Signal Transduction; Skeleton; Stem Cells; Transcription factors; Transfection
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-020-00731-6

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.