SIRT6 Regulates Protein Synthesis and Folding Through Nucleolar Remodeling

An important hallmark of aging-and particularly of neurodegeneration-is the loss of proteostasis, leading to cellular stress. However, the causal mechanisms driving this loss are unclear. We show that SIRT6 has a critical role in maintaining proteostasis. Mechanistically, SIRT6 negatively regulates global translation by controlling ribosomal genes, nucleolar function and TIP5 chromatin localization. SIRT6 deletion increases nucleolar size, rRNA production and protein translation. However, the expression of chaperones remains unchanged, failing to compensate for the excessive translation, leading to reduced folding capacity and production of aggregates. In vivo, we establish a C. elegans model (sir-2.4 KO) that shows reduced heat shock resistance and an accelerated age-dependent reduction in motility. Sir-2.4 depletion crossed with a neuron-specific polyQ strain led to premature motility loss and premature death. These results point to proteostasis-stress intolerance in the absence of SIRT6, that can be rescued by pharmacologically reducing protein translation rates. Our data suggest that SIRT6 deficiency results in proteostasis loss through nucleolar dysfunction. These results highlight that deficient proteostasis begins with chromatin dysregulation resulting in neurodegeneration.