Glucose intake hampers PKA-regulated HSP90 chaperone activity

• Main Authors: Yu-Chen Chen, 陳育辰
• Other Authors: Shu-Chun Teng
• Format: Others
• Language: en_US
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/32s44u

博士 === 國立臺灣大學 === 微生物學研究所 === 107 === Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake. ids2or ids2 phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation impedes its association with chaperone HSP90. Thus, PP2C and PKA may orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity. At another level associated with aging, ATM and ATR were previously thought to be key regulators of DNA damage but recently found to have an additional role in protein folding. We therefore tested whether ATM and ATR survey the quality of proteins via the regulatory mechanism of HSP90 chaperone complex. The results showed that ATM and ATR affect the activity of HSP90, but the detailed mechanism remains further study.