E3 ligase Trim63 promotes the chondrogenic differentiation of mesenchymal stem cells by catalyzing K27-linked cysteine ubiquitination of Myh11

Abstract Mesenchymal stem cells (MSCs) are multipotent stem cells that have a chondrogenic differentiation capacity. However, the molecular mechanism underlying the chondrogenic differentiation of MSCs has not been fully elucidated, which hinders further development of MSC-based cell therapies for cartilage repair in the clinic. Here, we showed that the E3 ubiquitin ligase Trim63 positively regulates the chondrogenic differentiation of MSCs by catalyzing the K27-linked cysteine ubiquitination of Myh11. Trim63 directly interacts with Myh11 and catalyzes K27-linked ubiquitination of cys382. Mutation of cys382 diminishes Trim63-catalyzed K27-linked ubiquitination and chondrogenic differentiation of MSCs. A deficiency in Trim63 significantly impairs the chondrogenic differentiation of MSCs. Trim63 enhances the repair of articular cartilage defects in vivo. Taken together, the results of our study demonstrated that Trim63 promotes the chondrogenic differentiation of MSCs by catalyzing K27-linked cysteine ubiquitination of Myh11, which provides an alternative therapeutic target for cartilage regeneration and repair.