PDF(Pubmed)
Abstract：
O-GlcNAcase (OGA) is the only human enzyme that catalyzes the hydrolysis (deglycosylation) of O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates. OGA has broad implications in many challenging diseases including cancer. However, its role in cell malignancy remains mostly unclear. Here, we report that a cancer-derived point mutation on the OGA\'s noncatalytic stalk domain aberrantly modulates OGA interactome and substrate deglycosylation toward a specific set of proteins. Interestingly, our quantitative proteomic studies uncovered that the OGA stalk domain mutant preferentially deglycosylated protein substrates with +2 proline in the sequence relative to the O-GlcNAcylation site. One of the most dysregulated substrates is PDZ and LIM domain protein 7 (PDLIM7), which is associated with the tumor suppressor p53. We found that the aberrantly deglycosylated PDLIM7 suppressed p53 gene expression and accelerated p53 protein degradation by promoting the complex formation with E3 ubiquitin ligase MDM2. Moreover, deglycosylated PDLIM7 significantly up-regulated the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. These findings revealed an important but previously unappreciated role of OGA\'s stalk domain in protein substrate recognition and functional modulation during malignant cell progression.
摘要：
O-GlcNAcase（OGA）是唯一催化来自多种蛋白质底物的O-连接的β-N-乙酰葡糖胺化（O-GlcNAcylation）的水解（去糖基化）的人类酶。OGA在包括癌症在内的许多具有挑战性的疾病中具有广泛的意义。然而,其在细胞恶性肿瘤中的作用尚不清楚。这里,我们报道,OGA的非催化茎结构域上的癌症衍生点突变异常地调节OGA相互作用组和底物对一组特定蛋白质的去糖基化作用.有趣的是,我们的定量蛋白质组学研究发现，相对于O-GlcNAcylation位点，OGA茎结构域突变体优先将序列中的+2脯氨酸去糖基化的蛋白质底物。最失调的底物之一是PDZ和LIM结构域蛋白7（PDLIM7），与肿瘤抑制因子p53有关。我们发现异常去糖基化的PDLIM7通过促进E3泛素连接酶MDM2的复合物形成来抑制p53基因表达并加速p53蛋白降解。此外，去糖基化的PDLIM7显著上调细胞表面富含肌动蛋白的膜突起，增强癌细胞的运动性和侵袭性。这些发现揭示了OGA茎结构域在恶性细胞进展过程中蛋白质底物识别和功能调节中的重要但以前未被认识的作用。
