# SIRT6 Regulates Protein Synthesis and Folding Through Nucleolar Remodeling

## TL;DR

SIRT6 helps maintain protein balance in cells by regulating ribosome production and preventing protein misfolding, which is crucial for preventing aging and neurodegeneration.

## Contribution

This study reveals a novel role of SIRT6 in proteostasis through nucleolar remodeling and ribosome regulation.

## Key findings

- SIRT6 deletion increases protein translation but not chaperone levels, leading to misfolded proteins and aggregation.
- A C. elegans model shows SIRT6 deficiency causes reduced heat shock resistance and accelerated aging symptoms.
- Reducing protein translation pharmacologically rescues the negative effects of SIRT6 deficiency.

## Abstract

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.

SIRT6 regulates proteostasis through nucleolar regulation. SIRT6 regulates (A) pre‐rRNA editing through nucleolar factors, as well as (B) rRNA transcription through TIP5 – and thus the NoRC – chromatin recruitment. (C) Once SIRT6 is depleted, the rRNA production and editing are increased, leading to a dramatic elevation in translation rates. However, chaperone levels remain unchanged, leading to the accumulation of misfolded proteins and aggregation upon SIRT6 deletion. (D) In a
C. elegans
‐based model, deleting the SIRT6 ortholog (sir‐2.4) leads to impaired heat shock resistance, as well as reduced motility upon overexpression of a neuronal aggregation‐prone protein (PolyQ40neuro
). (E) However, attenuating translation using 4PBA leads to the rescue of the sir‐2.

4KO;PolyQ40neuro
strain.