PT  - JOURNAL ARTICLE
AU  - Yu-Chen Chen
AU  - Pei-Heng Jiang
AU  - Hsuan-Ming Chen
AU  - Chang-Han Chen
AU  - Yi-Ting Wang
AU  - Yu-Ju Chen
AU  - Chia-Jung Yu
AU  - Shu-Chun Teng
TI  - Glucose intake hampers PKA-regulated HSP90 chaperone activity
AID  - 10.1101/376186
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 376186
4099  - http://biorxiv.org/content/early/2018/07/24/376186.short
4100  - http://biorxiv.org/content/early/2018/07/24/376186.full
AB  - 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. ids2Δ 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 of Ids2 impedes its association with chaperone HSP90. Thus, PP2C and PKA orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.