Deubiquitinating Enzyme USP8 Is Essential for Skeletogenesis by Regulating Wnt Signaling
UMass Chan AffiliationsLi Weibo Institute for Rare Diseases Research
Horae Gene Therapy Center
Shim Lab, Division of Rheumatology, Department of Medicine
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AbstractDisturbance in a differentiation program of skeletal stem cells leads to indecorous skeletogenesis. Growing evidence suggests that a fine-tuning of ubiquitin-mediated protein degradation is crucial for skeletal stem cells to maintain their stemness and osteogenic potential. Here, we demonstrate that the deubiquitinating enzyme (DUB) ubiquitin-specific protease 8 (USP8) stabilizes the Wnt receptor frizzled 5 (FZD5) by preventing its lysosomal degradation. This pathway is essential for Wnt/beta-catenin signaling and the differentiation of osteoprogenitors to mature osteoblasts. Accordingly, deletion of USP8 in osteoprogenitors (Usp8(Osx)) resulted in a near-complete blockade in skeletal mineralization, similar to that seen in mice with defective Wnt/beta-catenin signaling. Likewise, transplanting USP8-deficient osteoprogenitors under the renal capsule in wild-type secondary hosts did not to induce bone formation. Collectively, this study unveils an essential role for the DUB USP8 in Wnt/beta-catenin signaling in osteoprogenitors and osteogenesis during skeletal development.
Chaugule S, Kim JM, Yang YS, Knobeloch KP, He X, Shim JH. Deubiquitinating Enzyme USP8 Is Essential for Skeletogenesis by Regulating Wnt Signaling. Int J Mol Sci. 2021 Sep 24;22(19):10289. doi: 10.3390/ijms221910289. PMID: 34638628; PMCID: PMC8508692. Link to article on publisher's site