AMPK induces PIAS3 mediated SUMOylation of E3 ubiquitin ligase Smurf1 impairing osteogenic differentiation and traumatic heterotopic ossification

• Published in: Biochimica et biophysica acta. Molecular cell research 2024-10, Vol.1871 (7), p.119771, Article 119771
• Main Authors: Chen, Jie, Dang, Yan-miao, Liu, Meng-chao, Gao, Linqing, Guan, Tianshu, Hu, Anxin, Xiong, Lixia, Lin, Hui
• Format: Article
• Language: English
• Subjects: AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Cell Differentiation; HEK293 Cells; Heterotopic ossification; Humans; Mice; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Ossification, Heterotopic - genetics; Ossification, Heterotopic - metabolism; Ossification, Heterotopic - pathology; Osteogenesis - genetics; PIAS3; Protein Inhibitors of Activated STAT - genetics; Protein Inhibitors of Activated STAT - metabolism; Signal Transduction; Smurf1; SUMOylation; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0167-4889; 1879-2596; 1879-2596
• DOI: 10.1016/j.bbamcr.2024.119771

AMP-activated protein kinase (AMPK) is a typical sensor of intracellular energy metabolism. Our previous study revealed the role of activated AMPK in the suppression of osteogenic differentiation and traumatic heterotopic ossification, but the underlying mechanism remains poorly understood. The E3 ubiquitin ligase Smurf1 is a crucial regulator of osteogenic differentiation and bone formation. We report here that Smurf1 is primarily SUMOylated at a C-terminal lysine residue (K324), which enhances its activity, facilitating ALK2 proteolysis and subsequent bone morphogenetic protein (BMP) signaling pathway inhibition. Furthermore, SUMOylation of the SUMO E3 ligase PIAS3 and Smurf1 SUMOylation was suppressed during the osteogenic differentiation and traumatic heterotopic ossification. More importantly, we found that AMPK activation enhances the SUMOylation of Smurf1, which is mediated by PIAS3 and increases the association between PIAS3 and AMPK. Overall, our study revealed that Smurf1 can be SUMOylated by PIAS3, Furthermore, Smurf1 SUMOylation mediates osteogenic differentiation and traumatic heterotopic ossification through suppression of the BMP signaling pathway. This study revealed that promotion of Smurf1 SUMOylation by AMPK activation may be implicated in traumatic heterotopic ossification treatment. •Smurf1 is modified by SUMOylation at lysine residues K27,K72, and K324.•SUMOylation of Smurf1 enhance its function and suppresses BMP signaling pathways and its role in osteogenic differentiation.•AMPK interacts with Smurf1 and PIAS3 to elevate SUMOylated Smurf1 for a negative control in BMP signaling pathway.•Our study focuses on a novel Smurf1 function and verifies that SUMOylation of Smurf1 could be a potentially effective therapeutic strategy for HO in the future.