Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption
Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption
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Gasdermin D 通过重新连接破骨细胞骨吸收的内溶酶体途径来维持骨量
DOI：
10.1016/j.devcel.2022.09.013
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发表时间：
2022-10-24
影响因子：
11.8
通讯作者：
Wang, Di
中科院分区：
文献类型：
--
作者：
Li, Mobai;Yang, Dehang;Wang, Di
Gasdermin D（GSDMD）介导的焦亡诱导免疫原性细胞死亡并促进炎症。然而，GSDMD在组织稳态中的功能仍不清楚。在这里，我们确定了GSDMD在破骨细胞中的生理功能，通过非裂解性p20产生的蛋白质，防止骨丢失，以维持骨稳态。在RANKL诱导的破骨细胞生成的晚期阶段，GSDMD经历了依赖于RIPK 1和caspase-8/-3的裂解，以产生这种p20产物。缺乏gsdmd的破骨细胞表现出正常的分化，但增加骨吸收与过度的溶酶体活性。完全或骨髓特异性Gsdmd缺失的小鼠表现出增加的骨小梁丢失和更严重的衰老/卵巢切除诱导的骨质疏松症。GSDMD p20依赖于其寡聚化和通过结合磷脂酰肌醇3-磷酸（PI（3）P）控制磷酸肌醇转化，优先定位于早期内体和限制内-溶酶体运输和成熟。因此，我们已经确定了GSDMD的抗骨代谢功能作为溶酶体成熟和分泌的检查点，并将其与骨稳态和内体-溶酶体生物学联系起来。
Gasdermin D (GSDMD)-mediated pyroptosis induces immunogenic cell death and promotes inflammation. However, the functions of GSDMD in tissue homeostasis remain unclear. Here, we identify a physiological function of GSDMD in osteoclasts via a non-lytic p20-generated protein, which prevents bone loss to main-tain bone homeostasis. In the late stage of RANKL-induced osteoclastogenesis, GSDMD underwent cleav-age, which is dependent on RIPK1 and caspase-8/-3, to yield this p20 product. Gsdmd-deficient osteoclasts showed normal differentiation but enhanced bone resorption with excessive lysosomal activity. Mice with complete or myeloid-specific Gsdmd deletion exhibited increased trabecular bone loss and more severe ag-ing/ovariectomy-induced osteoporosis. GSDMD p20 was preferentially localized to early endosomes and limited endo-lysosomal trafficking and maturation, relying on its oligomerization and control of phosphoino-sitide conversion by binding to phosphatidylinositol 3-phosphate (PI(3)P). We have thus identified an anti-osteoclastic function of GSDMD as a checkpoint for lysosomal maturation and secretion and linked this to bone homeostasis and endosome-lysosome biology.