Periodic Reporting for period 4 - StemProteostasis (Mediation of stem cell identity and aging by proteostasis)
Berichtszeitraum: 2021-01-01 bis 2021-06-30
Beyond the proteasome, we defined other upregulated proteostasis mechanisms in hESCs/iPSCs and proved their role as anti-aging factors. First, we discovered that hESCs have upregulated activity of the TRiC/CCT complex, a chaperonin that facilitates the folding of 15% of the human proteome. We observed that somatic overexpression of CCT8, a TRiC/CCT subunit, extends C. elegans lifespan and ameliorates HD-related changes (Noormohammadi, Nature Communications, 2016). In hESCs, we also found increased expression of specific RNA-binding proteins (i.e. cold-shock enzymes) required for stem cell function (Lee et al, Nature Communications, 2017). Notably, these RNA-binding proteins determined C. elegans longevity through their activity in germline stem cells (Lee et al, Nature Metabolism 2019). Importantly, we found that a collapse in germline proteostasis leads to systemic mitochondrial alterations in tissues such as muscle and neurons through long-range signals. Subsequently, these alterations increased aggregation of HD and ALS-related proteins in somatic tissues such as neurons (Calculli & Lee et al, Science Advances, 2021).
Finally, we examined whether proteostasis regulates viability of plant stem cells in Arabidopsis thaliana. In contrast to their differentiated counterparts, root stem cells could prevent the accumulation of aggregated proteins even under proteotoxic stress conditions such as heat stress or proteasome inhibition. Notably, endogenous high levels of the TRiC/CCT complex were required for plant stem cell maintenance and their remarkable ability to suppress protein aggregation. Moreover, overexpression of CCT8 was sufficient to ameliorate protein aggregation in differentiated cells and confer resistance to proteotoxic stress in plants. Together, our results established enhanced proteostasis in stem cells as an important requirement for plants to persist under extreme environmental conditions and reach extreme long ages (Llamas et al, Aging Cell 2021).