Center for Integrative Genomics, University of Lausanne, Switzerland.
Cell. 2011 Feb 4;144(3):376-88. doi: 10.1016/j.cell.2010.12.030.
The human epigenetic cell-cycle regulator HCF-1 undergoes an unusual proteolytic maturation process resulting in stably associated HCF-1(N) and HCF-1(C) subunits that regulate different aspects of the cell cycle. Proteolysis occurs at six centrally located HCF-1(PRO)-repeat sequences and is important for activation of HCF-1(C)-subunit functions in M phase progression. We show here that the HCF-1(PRO) repeat is recognized by O-linked β-N-acetylglucosamine transferase (OGT), which both O-GlcNAcylates the HCF-1(N) subunit and directly cleaves the HCF-1(PRO) repeat. Replacement of the HCF-1(PRO) repeats by a heterologous proteolytic cleavage signal promotes HCF-1 proteolysis but fails to activate HCF-1(C)-subunit M phase functions. These results reveal an unexpected role of OGT in HCF-1 proteolytic maturation and an unforeseen nexus between OGT-directed O-GlcNAcylation and proteolytic maturation in HCF-1 cell-cycle regulation.
人类表观遗传细胞周期调节剂 HCF-1 经历了一个不寻常的蛋白水解成熟过程，导致稳定相关的 HCF-1(N) 和 HCF-1(C)亚基，调节细胞周期的不同方面。蛋白水解发生在六个中央定位的 HCF-1(PRO)-重复序列中，对于激活 HCF-1(C)亚基在 M 期进展中的功能非常重要。我们在这里表明，HCF-1(PRO)重复序列被 O 连接的β-N-乙酰葡萄糖胺转移酶 (OGT)识别，OGT 既对 HCF-1(N)亚基进行 O-GlcNAcylation，又直接切割 HCF-1(PRO)重复序列。用异源蛋白水解切割信号取代 HCF-1(PRO)重复序列可促进 HCF-1 蛋白水解，但不能激活 HCF-1(C)亚基 M 期功能。这些结果揭示了 OGT 在 HCF-1 蛋白水解成熟中的意外作用，以及 OGT 指导的 O-GlcNAcylation 和 HCF-1 细胞周期调节中的蛋白水解成熟之间的意外联系。
