PDF(Pubmed)
Abstract：
The OSGEP gene encodes O-sialoglycoprotein endopeptidase, a catalytic unit of the highly conserved KEOPS complex (Kinase, Endopeptidase, and Other Proteins of small Size) that regulates the second biosynthetic step in the formation of N-6-threonylcarbamoyladenosine (t6A). Mutations in KEOPS cause Galloway-Mowat syndrome (GAMOS), whose cellular function in mammals and underlying molecular mechanisms are not well understood. In this study, we utilized lentivirus-mediated OSGEP knockdown to generate OSGEP-deficient human embryonic stem cells (hESCs). OSGEP-knockdown hESCs exhibited reduced stemness factor expression and G2/M phase arrest, indicating a potential role of OSGEP in the regulation of hESC fate. Additionally, OSGEP silencing led to enhanced protein synthesis and increased aggregation of proteins, which further induced inappropriate autophagy, as evidenced by the altered expression of P62 and the conversion of LC3-I to LC3-II. The above findings shed light on the potential involvement of OSGEP in regulating pluripotency and differentiation in hESCs while simultaneously highlighting its crucial role in maintaining proteostasis and autophagy, which may have implications for human disease.
摘要：
OSGEP基因编码O-唾液酸糖蛋白内肽酶，高度保守的KEOPS复合物的催化单元(激酶，内肽酶,和其他小尺寸蛋白质），可调节N-6-苏酰基氨基甲酰基腺苷（t6A）形成中的第二个生物合成步骤。KEOPS突变导致Galloway-Mowat综合征（GAMOS），其在哺乳动物中的细胞功能和潜在的分子机制尚不清楚。在这项研究中,我们利用慢病毒介导的OSGEP敲低产生OSGEP缺陷型人胚胎干细胞(hESCs).OSGEP敲低hESC表现出干性因子表达降低和G2/M期阻滞，表明OSGEP在调节hESC命运中的潜在作用。此外,OSGEP沉默导致蛋白质合成增强和蛋白质聚集增加，这进一步诱导了不适当的自噬，如P62的表达改变和LC3-I向LC3-II的转化所证明的。上述发现揭示了OSGEP在调节hESCs多能性和分化中的潜在参与，同时强调了其在维持蛋白质平衡和自噬中的关键作用。这可能对人类疾病有影响。
