Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Pei-Heng Jiang
Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Hsuan-Ming Chen
Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Chang-Han Chen
Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Yi-Ting Wang
Institute of Chemistry, Academia Sinica, Taipei, Taiwan
Yu-Ju Chen
Institute of Chemistry, Academia Sinica, Taipei, Taiwan
Chia-Jung Yu
Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Thoracic Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Center of Precision Medicine, National Taiwan University, Taipei, Taiwan
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 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.
