Abstract
The Protein kinase A (PKA) and Sch9 regulates cell growth as well as lifespan in Saccharomyces cerevisiae. Maf1 is a RNA polymerase III (PolIII) inhibitor that tailors 5S rRNA and tRNA production in response to various environmental cues. Both PKA and Sch9 have been shown to phosphorylate Maf1 in vitro at similar amino acids, suggesting a redundancy in Maf1 regulation. However, here we find that activating PKA by bcy1 deletion cannot replace Sch9 for Maf1 phosphorylation and cytoplasmic retention; instead, such modulation lowers Maf1 protein levels. Consistently, loss of MAF1 or constitutive PKA activity reverses the stress resistance and the extended lifespan of sch9Δ cells. Overexpression of MAF1 partially rescues the extended lifespan of sch9Δ in bcy1Δsch9Δ mutant, suggesting that PKA suppresses sch9Δ longevity at least partly through Maf1 abundance. Constitutive PKA activity also reverses the reduced tRNA synthesis and slow growth of sch9Δ, which, however, is not attributed to Maf1 protein abundance. Therefore, regulation of lifespan and growth can be decoupled. Together, we reveal that lifespan regulation by PKA and Sch9 are mediated by Maf1 through distinct mechanisms.
Highlights
Protein kinase A (PKA) and Sch9 belong to the ACG family of Serine/Threonine kinase [1]
In response to nutrient or growth factors, PKA is activated by cyclic AMP and transduces the growth signals to ribosomal biogenesis machineries e.g. RNA polymerases (Pol Is) including Pol I that is responsible for synthesis of ribosomal RNA, Pol II ribosomal protein (RP) and polymerase III (Pol III) transfer RNAs
These results suggest that Sch9 but not PKA is the major kinase that phosphorylates and controls Maf1 subcellular localization in vivo
Summary
Protein kinase A (PKA) and Sch belong to the ACG family of Serine/Threonine kinase [1]. These two kinases are highly conserved throughout evolution [2]. Sch is phosphorylated by TORC1 [3], the yeast counterpart of mTORC1 Both kinases are well known to regulate cell growth and proliferation, largely through enhancing ribosome biogenesis [4, 5]. Sch9/S6K1 targets ribosomal protein S6 and other regulators to modulate protein translation initiation and ribosome biogenesis. Both kinases have been implicated in cancerous transformation [6, 7]
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