A post-translational modification cascade employing HDAC9-PIASy-RNF4 axis regulates chondrocyte hypertrophy by modulating Nkx3.2 protein stability.
While Nkx3.2/Bapx1 promotes chondrogenic differentiation and plays a role in maintaining chondrocyte viability and suppressing chondrocyte hypertrophy, the regulatory mechanisms of Nkx3.2 remain poorly understood. Here we show that p300- and HDAC9-induced Nkx3.2 acetylation and de-acetylation, respectively, play critical roles in controlling Nkx3.2 protein stability. In addition, we also found that HDAC9-dependent de-acetylation of Nkx3.2 triggers PIASy-mediated sumoylation and subsequent RNF4-mediated SUMO-targeted ubiquitination. Furthermore, we demonstrate that Nkx3.2 regulation by HDAC9 can be linked to the management of chondrocyte survival and hypertrophic maturation during cartilage development. Finally, our results together reveal a novel mechanism of protein stability control involving complex interplay between acetylation, de-acetylation, sumoylation, and ubiquitination, and suggest that this post-translational modification of Nkx3.2 employing HDAC9-PIASy-RNF4 axis plays a crucial role in controlling chondrocyte viability and hypertrophic maturation during skeletal development in vertebrates.
Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
Hye-Jeong
HJ
Choi
Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
Seongran
S
Kwon
Department of Biochemistry, Yonsei University, Seoul, Republic of Korea. Electronic address: kimdw@yonsei.ac.kr.
Dae-Won
DW
Kim
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy; D008239:Lysine / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
D018398:Homeodomain Proteins; C491536:NKX3-2 protein, human; D009687:Nuclear Proteins; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; C114070:RNF4 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; C110550:HDAC1 protein, human; C486544:HDAC9 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D008239:Lysine
Acetylation-dependent sumoylation; Cartilage Development; HDAC9; Nkx3.2; Sumoylation-dependent ubiquitination