HSP90 drives the Rab11a‐mediated vesicular transport of the cell surface receptors in osteoclasts. (16th September 2022)

• Record Type: Journal Article
• Authors: Tran, Manh Tien; Okusha, Yuka; Htike, Kaung; Sogawa, Chiharu; Eguchi, Takanori; Kadowaki, Tomoko; Sakai, Eiko; Tsukuba, Takayuki; Okamoto, Kuniaki
• Is Part Of: Cell biochemistry and function. Volume 40:Number 8(2022)
• Page Start: 838
• Page End: 855
• Publication Date: 2022-09-16
• Subjects: heat shock protein 90 (HSP90) -- osteoclasts -- Rab11a -- vesicular transport; Cytochemistry -- Periodicals; Cell metabolism -- Periodicals; Biochemistry -- Periodicals; Cytology -- Periodicals; 572
• DOI: 10.1002/cbf.3745
• Languages: English
• ISSNs: 0263-6484

Abstract

Abstract: Rab11a, which ubiquitously localizes to early and recycling endosomes, is required for regulating the vesicular transport of cellular cargos. Interestingly, our previous study revealed that Rab11a served as a negative regulator of osteoclastogenesis by facilitating the lysosomal proteolysis of (1) colony‐stimulating factor‐1 (c‐fms) receptor and (2) receptor activator of nuclear factor‐κB (RANK) receptor, thereby resulting in inhibition of osteoclast (OC) differentiation, maturation, and bone‐resorbing activity. However, the molecular mechanisms of how Rab11a negatively affected osteoclastogenesis were largely unknown. Heat shock protein (HSP90), including two isoforms HSP90α and HSP90β, necessitates the stability, maturation, and activity of a broad range of its clients, and is essentially required for a vast array of signal transduction pathways in nonstressful conditions. Furthermore, cumulative evidence suggests that HSP90 is a vital element of the vesicular transport network. Indeed, our recent study revealed that HSP90, a novel effector protein of Rab11b, modulated Rab11b‐mediated osteoclastogenesis. In this study, we also found that Rab11a interacted with both HSP90α and HSP90β in OCs. Upon blockade of HSP90 ATPase activity by a specific inhibitor(17‐allylamino‐demethoxygeldanamycin), we showed that (1) the ATPase domain of HSP90 was a prerequisite for the interaction between HSP90 and Rab11a, and (2) the interaction of HSP90 to Rab11a sufficiently maintained the inhibitory effects of Rab11a on osteoclastogenesis. Altogether, our findings undoubtedly indicate a novel role of HSP90 in regulating Rab11a‐mediated osteoclastogenesis. Significance statement: Increasing evidence elucidates that Rab GTPases play a central role in regulating the vesicular transport of subcellular cargos and osteoclastogenesis. Of these, Rab11a was shown to negatively regulate osteoclastogenesis mainly via controlling lysosome‐induced proteolysis of cell surface receptors, c‐fms, and receptor activator of nuclear factor‐κB (RANK) in OCs. Nevertheless, the specific mechanisms underlying the Rab11a‐mediated regulation of osteoclastogenesis are obscure. In this study, we, for the first time, revealed that heat‐shock protein 90 (HSP90) served as a novel effector protein of Rab11a. HSP90 interacted with Rab11a and regulated Rab11a's physiological functions in this process. Specifically, HSP90 accelerated the lysosome‐induced proteolysis of c‐fms and RANK surface receptors, subsequently abolishing c‐fos/nuclear factor of activated T‐cell cytoplasmic‐1 signaling pathways, deteriorating OC differentiation, maturation, and bone resorption, thereby contributing to the dynamic regulation of bone remodeling.