A novel role of HSP90 in regulating osteoclastogenesis by abrogating Rab11b-driven transport
A novel role of HSP90 in regulating osteoclastogenesis by abrogating Rab11b-driven transport
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DOI：
10.1016/j.bbamcr.2021.119096
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发表时间：
2021-07-13
影响因子：
5.1
通讯作者：
Okamoto, Kuniaki
中科院分区：
文献类型：
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作者：
Manh Tien Tran;Okusha, Yuka;Okamoto, Kuniaki
热休克蛋白90（Heat shock protein 90，HSP 90）是一种高度保守的分子伴侣，在多种客户蛋白的折叠、激活和组装中起着关键作用。此外，热休克蛋白90最近出现作为一个重要的调节囊泡运输的细胞蛋白质。在我们之前的研究中，我们发现Rab 11b通过早期内体-晚期内体-溶酶体轴促进c-fms和RANK表面受体的溶酶体蛋白水解来负调节破骨细胞生成。在这项研究中，使用从小鼠巨噬细胞样RAW-D细胞分化的破骨细胞体外模型，我们发现Rab 11b与HSP 90亚型，HSP 90 α（HSP 90 α）和HSP 90 β（HSP 90 β）相互作用，表明Rab 11b是HSP 90客户端。利用HSP 90 ATP酶活性的特异性阻断剂17-烯丙氨基-去甲氧基格尔德霉素（17-AAG），我们发现HSP 90 ATP酶结构域是维持破骨细胞中HSP 90与Rab 11b相互作用所必需的。然而，其ATP酶活性不是调节内源性Rab 11b周转所必需的。有趣的是，通过HSP 90靶向小干扰RNA（siHSP 90）或17-AAG阻断HSP 90和Rab 11b之间的相互作用，通过抑制Rab 11b介导的c-fms和RANK表面受体经由早期内体-晚期内体-溶酶体轴向溶酶体的转运，减轻破骨细胞中Rab 11b介导的这些表面受体的蛋白水解。基于我们的观察，我们提出了一种HSP 90/Rab 11b介导的破骨细胞生成的调节机制，通过直接调节破骨细胞中的c-fms和RANK表面受体，从而有助于维持骨稳态。
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that plays a pivotal role in folding, activating and assembling a variety of client proteins. In addition, HSP90 has recently emerged as a crucial regulator of vesicular transport of cellular proteins. In our previous study, we revealed Rab11b negatively regulated osteoclastogenesis by promoting the lysosomal proteolysis of c-fms and RANK surface receptors via the axis of early endosome-late endosome-lysosomes. In this study, using an in vitro model of osteoclasts differentiated from murine macrophage-like RAW-D cells, we revealed that Rab11b interacted with both HSP90 isoforms, HSP90 alpha (HSP90 alpha) and HSP90 beta (HSP90 beta), suggesting that Rab11b is an HSP90 client. Using at specific blocker for HSP90 ATPase activity, 17-allylamino-demethoxygeldanamycin (17-AAG), we found that the HSP90 ATPase domain is indispensable for maintaining the interaction between HSP90 and Rab11b in osteoclasts. Nonetheless, its ATPase activity is not required for regulating the turnover of endogenous Rab11b. Interestingly, blocking the interaction between HSP90 and Rab11b by either HSP90-targeting small interfering RNA (siHSP90) or 17-AAG abrogated the inhibitory effects of Rab11b on osteoclastogenesis by suppressing the Rab11b-mediated transport of c-fms and RANK surface receptors to lysosomes via the axis of early endosome-late endosome-lysosomes, alleviating the Rab11b-mediated proteolysis of these surface receptors in osteoclasts. Based on our observations, we propose a HSP90/Rab11b-mediated regulatory mechanism for osteoclastogenesis by directly modulating the c-fms and RANK surface receptors in osteoclasts, thereby contributing to the maintenance of bone homeostasis.