State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China.
Frontiers Science Center for Cell Responses, College of Life Science, Nankai University, Tianjin, 300071, China.
Stem Cell Res Ther. 2024 Jun 21;15(1):180. doi: 10.1186/s13287-024-03789-y.
Telomeres consist of repetitive DNA sequences at the chromosome ends to protect chromosomal stability, and primarily maintained by telomerase or occasionally by alternative telomere lengthening of telomeres (ALT) through recombination-based mechanisms. Additional mechanisms that may regulate telomere maintenance remain to be explored. Simultaneous measurement of telomere length and transcriptome in the same human embryonic stem cell (hESC) revealed that mRNA expression levels of UBQLN1 exhibit linear relationship with telomere length.
In this study, we first generated UBQLN1-deficient hESCs and compared with the wild-type (WT) hESCs the telomere length and molecular change at RNA and protein level by RNA-seq and proteomics. Then we identified the potential interacting proteins with UBQLN1 using immunoprecipitation-mass spectrometry (IP-MS). Furthermore, the potential mechanisms underlying the shortened telomeres in UBQLN1-deficient hESCs were analyzed.
We show that Ubiquilin1 (UBQLN1) is critical for telomere maintenance in human embryonic stem cells (hESCs) via promoting mitochondrial function. UBQLN1 deficiency leads to oxidative stress, loss of proteostasis, mitochondria dysfunction, DNA damage, and telomere attrition. Reducing oxidative damage and promoting mitochondria function by culture under hypoxia condition or supplementation with N-acetylcysteine partly attenuate the telomere attrition induced by UBQLN1 deficiency. Moreover, UBQLN1 deficiency/telomere shortening downregulates genes for neuro-ectoderm lineage differentiation.
Altogether, UBQLN1 functions to scavenge ubiquitinated proteins, preventing their overloading mitochondria and elevated mitophagy. UBQLN1 maintains mitochondria and telomeres by regulating proteostasis and plays critical role in neuro-ectoderm differentiation.
端粒由染色体末端的重复 DNA 序列组成，可保护染色体稳定性，主要由端粒酶或偶尔通过基于重组的机制通过端粒的替代性端粒延长（ALT）来维持。仍需要探索可能调节端粒维持的其他机制。在同一人类胚胎干细胞（hESC）中同时测量端粒长度和转录组，发现 UBQLN1 的 mRNA 表达水平与端粒长度呈线性关系。
本研究首先生成 UBQLN1 缺陷型 hESC，并与野生型（WT）hESC 进行比较，通过 RNA-seq 和蛋白质组学分析 RNA 和蛋白质水平的端粒长度和分子变化。然后，我们使用免疫沉淀-质谱（IP-MS）鉴定与 UBQLN1 相互作用的潜在蛋白质。此外，还分析了 UBQLN1 缺陷型 hESC 中端粒缩短的潜在机制。
我们表明，泛素蛋白（UBQLN1）通过促进线粒体功能对于人类胚胎干细胞（hESC）中的端粒维持至关重要。UBQLN1 缺陷导致氧化应激、蛋白质稳态丧失、线粒体功能障碍、DNA 损伤和端粒损耗。在低氧条件下培养或补充 N-乙酰半胱氨酸以减少氧化损伤和促进线粒体功能，部分减轻了 UBQLN1 缺陷引起的端粒损耗。此外，UBQLN1 缺陷/端粒缩短下调神经外胚层谱系分化的基因。
总之，UBQLN1 可清除泛素化蛋白，防止其过度加载线粒体并增加线粒体自噬。UBQLN1 通过调节蛋白质稳态来维持线粒体和端粒，并在神经外胚层分化中发挥关键作用。
