Site-1 protease controls osteoclastogenesis by mediating LC3 transcription
Site-1 protease controls osteoclastogenesis by mediating LC3 transcription
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DOI：
10.1038/s41418-020-00731-6
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发表时间：
2021-01
影响因子：
12.4
通讯作者：
Ze-yu Zheng;Xuyang Zhang;Bao Huang;Jun-hui Liu;Xiaoan Wei;Zhi Shan;Hao Wu;Zhen-hua Feng;Yi-lei Chen;S. Fan;F. Zhao;Jian Chen
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文献类型：
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作者：
Ze-yu Zheng;Xuyang Zhang;Bao Huang;Jun-hui Liu;Xiaoan Wei;Zhi Shan;Hao Wu;Zhen-hua Feng;Yi-lei Chen;S. Fan;F. Zhao;Jian Chen
S1蛋白酶（Site-1 protease，S1 P）是一种位于高尔基体的蛋白质，能激活独特的膜结合的潜在转录因子，在内质网应激、脂质代谢、炎症反应和溶酶体功能中起着不可或缺的作用。一例S1 P突变患者表现出严重的骨骼发育不良伴脊柱后凸、面部畸形和鸡胸。然而，S1 P是否通过影响破骨细胞生成来调节骨重建仍然是一个谜。在这里，我们表明，S1 P确实是一个积极的破骨细胞生成的调节。与野生型同窝小鼠相比，小鼠中的S1 P消融导致显著的骨质疏松。从机制上讲，S1 P在破骨细胞生成过程中表现出上调，并被鉴定为miR-9- 5 p的直接靶点。骨髓单核细胞（BMPs）中S1 P缺失抑制ATF 6和SREBP 2成熟，随后阻碍CHOP/SREBP 2复合物诱导的LC 3表达和自噬通量。因此，LC 3腺病毒转染明显挽救了S1 P缺陷型BMSCs中的破骨细胞生成。然后，我们通过免疫共沉淀（Co-IP）和分子对接鉴定了CHOP和SREBP 2之间的相互作用区域。此外，S1 P缺失或抑制剂在体内有效地挽救了卵巢切除（OVX）和LPS诱导的骨丢失。总的来说，我们发现S1 P以LC 3依赖的方式调节破骨细胞分化，因此是骨质疏松症的潜在治疗靶点。
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.