Insights into Cellular Stress Revealed by SIRT7

Aging was once thought to be an inexorable process, driven by wear and tear that steadily accumulates in cells. However, we have now come to the realization that aging is subject to modulation by genetic pathways, including the insulin/IGF-1 pathway, the mTOR(definition) pathway, and sirtuins. A commonality among these pathways is that they exert their pro-longevity and pro-health effects through responding to stressors, such as diet, oxidative stress, or protein-folding stress, and initiating a self-protective program in the cell. Sirtuins have been shown to play a major role in the cellular response to calorie restriction and oxidative stress. However, their role in protein homeostasis and in particular, the response to stress from unfolded proteins has not been well-characterized. We explored this topic by studying the role of SIRT7, a nuclear member of the mammalian sirtuin family, in responding to protein-folding stress in the endoplasmic reticulum (ER) and in mitochondria. We found that SIRT7 plays a pivotal role in the response to ER stress and mitochondrial stress by inhibiting the transcription of ribosomal subunits and mitochondrial ribosomal subunits, which results in a reduction in translation, allowing more time for proper protein folding. We found that SIRT7 mediates its effects by binding to the transcription factors Myc and NRF-1, which are master regulators of ribosomal subunits and mitochondrial biogenesis respectively. Our study suggests that the stress response mediated by SIRT7 at the cellular level may have important implications for obesity-associated diseases and hematopoietic stem cell function.