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标题：IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation
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作者：Vishwa Deepak ; Shu-ting Yang ; Ziqing Li 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：26
DOI：10.1073/pnas.2201490119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Osteoclasts (OCs) are the sole bone resorbing cells indispensable for bone remodeling. Hence, understanding of novel signaling modulators regulating OC formation is clinically important. Intraflagellar transport (IFT) proteins are important for cilia, cell signaling, and organ development. It remains unclear whether IFT80 plays a role in OCs. This study uncovers an intriguing role of IFT80 in OCs where the ciliary protein regulates the stability of critical OC factor TRAF6 via Cbl-b and thereby contributes to the maintenance of OC numbers. These findings provide further basis for understanding and delineating the role of IFT proteins in OCs that may provide new strategies for treatment of osteolytic diseases. Excess bone loss due to increased osteoclastogenesis is a significant clinical problem. Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation. The role of IFT80, an IFT complex B protein, in osteoclasts (OCs) is completely unknown. Here, we demonstrate that deletion of IFT80 in the myeloid lineage led to increased OC formation and activity accompanied by severe bone loss in mice. IFT80 regulated OC formation by associating with Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) to promote protein stabilization and proteasomal degradation of tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6). IFT80 knockdown resulted in increased ubiquitination of Cbl-b and higher TRAF6 levels, thereby hyperactivating the receptor activator of nuclear factor-κβ (NF-κβ) ligand (RANKL) signaling axis and increased OC formation. Ectopic overexpression of IFT80 rescued osteolysis in a calvarial model of bone loss. We have thus identified a negative function of IFT80 in OCs.
关键词：enosteoclastIFT80boneosteoblast