H9 hESC neuronal differentiation time course

Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that somatic increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington’s disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.

人类胚胎干细胞（human embryonic stem cells）可在维持未分化状态的前提下无限增殖，因此在体外培养中具有永生性。这种特性要求必须规避任何可能损害干细胞身份的蛋白质稳态（proteostasis）失衡。本研究发现，人类多能干细胞会增强TRiC/CCT复合物的组装——该复合物是一种伴侣蛋白（chaperonin），可介导10%的蛋白质组（proteome）进行折叠。我们证实，仅异位表达单个亚基CCT8即可提升TRiC/CCT复合物的组装效率。此外，增强的TRiC/CCT复合物是规避突变亨廷顿蛋白聚集的必要条件。我们进一步发现，在秀丽隐杆线虫（Caenorhabditis elegans）的体细胞组织中增强表达CCT8，可通过TRiC/CCT依赖的方式延长其寿命。异位表达CCT8还可改善衰老相关的蛋白质稳态衰退，并纠正亨廷顿病线虫模型中的蛋白质稳态缺陷。本研究结果表明，蛋白质稳态是连接机体寿命与人类胚胎干细胞永生性的共同核心原理。