Abstract
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.
Highlights
Aging is a complex process in which cells gradually lose their ability to execute regular functions and organs show increased susceptibility to disease (Harman, 1981)
RLS denotes the number of daughter cells that a single mother cell can generate before senescence, representing the division potential of the mother cell (Mortimer and Johnston, 1959), whereas chronological lifespan (CLS) refers to the length of time for which yeast cells remain viable in a non-dividing state (Longo and Fabrizio, 2012)
The rightward shift in the 2% glucose/0.5% glucose ratio of phosphopeptides in Figure 1—figure supplement 1B indicated that the abundance of phosphopeptides decreased under 0.5% glucose, which is in agreement with that many kinases, such as Tor, Sch9, and PKA, were downregulated under Calorie restriction (CR) (Wei et al, 2008)
Summary
Aging is a complex process in which cells gradually lose their ability to execute regular functions and organs show increased susceptibility to disease (Harman, 1981). The causes of aging have been attributed to nine hallmarks (Lopez-Otın et al, 2013). Calorie restriction (CR) is the most effective intervention known to extend lifespan (McCay et al, 1989), improve organism function, and retard cell senescence in a variety of species from yeast to mammals (McCay et al, 1989; de Cabo et al, 2015; de Cabo et al, 2014; Lin et al, 2002). RLS denotes the number of daughter cells that a single mother cell can generate before senescence, representing the division potential of the mother cell (Mortimer and Johnston, 1959), whereas CLS refers to the length of time for which yeast cells remain viable in a non-dividing state (Longo and Fabrizio, 2012)
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