Dual functions of yeast 14-3-3 protein Bmh1 in life span regulation .

摘要

Aging is a complex process and is regulated at different levels. Identification of novel longevity regulators is crucial for further development of the aging field. Here, we identified one of the yeast 14-3-3 proteins, Bmh1, as a longevity regulator. 14-3-3 proteins are conserved chaperone-like proteins that are important in many cellular processes. Interestingly, both deleting and over-expressing Bmh1 extend life span. Our studies suggest that bmh1Delta and Bmh1 over-expression (Bmh1-oe) extend life span by different mechanisms.;First, we show that deleting Bmh1extends chronological life span (CLS) by activating stress response. Enhanced stress response has been suggested to promote longevity in many species. We have shown that bmh1Delta -induced heat resistance and CLS extension require general stress response transcription factors Msn2, Msn4, and Rim15. The bmh1Delta mutant also displays decreased reactive oxygen species (ROS) level. We have shown that BMH1 genetically interacts with CR and conserved nutrient-sensing TOR- and PKA-signaling pathways to regulate life span. Interestingly, the level of phosphorylated Ser238 on Bmh1 increases during chronological aging, which is delayed by CR or by reduced TOR activities. In addition, PKA can directly phosphorylate Ser238 on Bmh1. The status of Bmh1 phosphorylation is therefore likely to play important roles in life span regulation.;Next, we have shown that Bmh1-oe increases mitochondrial respiration and promotes antioxidant enzyme activities, leading to lower ROS level and life span extension. Accumulation of ROS has been suggested as one of the major causes of aging. Here we show that Bmh1-oe only extends life span in cells that are metabolically active, and Bmh1-oe induced CLS extension requires functional mitochondria. Furthermore, Bmh1-oe cells have increased mitochondrial activities such as increased oxygen consumption rate and higher mitochondrial DNA content. Bmh1-oe also delays the age-dependent changes in mitochondrial structure. Interestingly, intracellular ROS level in Bmh1-oe cells is lower than that in control cells. Bmh1-oe displays higher SOD activities at stationary phase, which might contribute to the lower ROS level in Bmh1-oe cells. We also demonstrate that Bmh1-oe extends RLS, which requires the Sir2 family.;In conclusion, we propose that yeast 14-3-3 protein Bmh1 acts as a double-edged sword to regulate longevity.