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. 2021 Oct;36(10):2053-2064.
doi: 10.1002/jbmr.4398. Epub 2021 Jul 1.

Rictor Is a Novel Regulator of TRAF6/TRAF3 in Osteoclasts

Song Xu  1   2 , Shihai Li  1 , Xianming Liu  1 , Kang Tan  1 , Jiahuan Zhang  1 , Kai Li  3 , Xiaochun Bai  1 , Yue Zhang  1
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Free article

Rictor Is a Novel Regulator of TRAF6/TRAF3 in Osteoclasts

Song Xu et al. J Bone Miner Res. 2021 Oct.
Free article

Abstract

Tumor necrosis factor receptor-associated factors (TRAFs) are crucial for receptor activator of nuclear factor-κB (RANK) activation in osteoclasts. However, the upstream mechanisms of TRAF members in the osteoclastic lineage remain largely unknown. Here, we demonstrated that Rictor, a key component of mechanistic target of rapamycin complex 2 (mTORC2), was crucial for TRAF6/TRAF3 expression in osteoclasts. Our ex vivo and in vivo studies showed that Rictor ablation from the osteoclastic lineage reduced osteoclast numbers and increased bone mass in mice. Mechanistically, we found that Rictor ablation restricted osteoclast formation, which disrupted TRAF6 stability and caused autophagy block in a manner distinct from mTORC1, resulting in reduced TRAF3 degradation. Boosting TRAF6 expression or knockdown of TRAF3 levels in Rictor-deficient cells could both overcome the defect. Moreover, Rictor could interact with TRAF6 upon RANK ligand (RANKL) stimulation and loss of Rictor impaired TRAF6 stability and promoted its ubiquitinated degradation. These findings established an innovative link between Rictor, TRAF protein levels, and autophagic block. More importantly, mTOR complexes in the osteoclastic lineage are likely switches for coordinating TRAF6 and TRAF3 protein levels, and Rictor may function as an essential upstream regulator of TRAF6/TRAF3 that is partially independent of mTORC1 activity. Inhibitors targeting Rictor may therefore be valuable for preventing or treating osteoclast-related diseases. © 2021 American Society for Bone and Mineral Research (ASBMR).

Keywords: AUTOPHAGIC FLUX; OSTEOCLAST; RICTOR; TRAF3; TRAF6.

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References

    1. Henriksen K, Bollerslev J, Everts V, Karsdal MA. Osteoclast activity and subtypes as a function of physiology and pathology-implications for future treatments of osteoporosis. Endocr Rev. 2011;32(1):31-63.
    1. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337-342.
    1. Darnay BG, Besse A, Poblenz AT, Lamothe B, Jacoby JJ. TRAFs in RANK signaling. Adv Exp Med Biol. 2007;597:152-159.
    1. Lalani AI, Zhu S, Gokhale S, Jin J, Xie P. TRAF molecules in inflammation and inflammatory diseases. Curr Pharmacol Rep. 2018;4(1):64-90.
    1. Mukundan L, Bishop GA, Head KZ, Zhang L, Wahl LM, Suttles J. TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages. J Immunol. 2005;174(2):1081-1090.

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