Abstract
Target of rapamycin complex 1 (TORC1) phosphorylates autophagy-related Atg13 and represses autophagy under nutrient-rich conditions. However, when TORC1 becomes inactive upon nutrient depletion or treatment with the TORC1 inhibitor rapamycin, Atg13 dephosphorylation occurs rapidly, and autophagy is induced. At present, the phosphatases involved in Atg13 dephosphorylation remain unknown. Here, we show that two protein phosphatase 2A (PP2A) phosphatases, PP2A-Cdc55 and PP2A-Rts1, which are activated by inactivation of TORC1, are required for sufficient Atg13 dephosphorylation and autophagy induction after TORC1 inactivation in budding yeast. After rapamycin treatment, dephosphorylation of Atg13, activation of Atg1 kinase, pre-autophagosomal structure (PAS) formation and autophagy induction are all impaired in PP2A-deleted cells. Conversely, overexpression of non-phosphorylatable Atg13 suppressed defects in autophagy in PP2A mutant. This study revealed that the orchestrated action of PP2A antagonizes Atg13 phosphorylation and promotes autophagy after the inactivation of TORC1.
Highlights
Autophagy degrades cytoplasmic components in lysosomes/vacuoles, which is a conserved system from the yeast to mammalian cells [1, 2]
We investigated which protein phosphatases are involved in autophagy induction via inactivation of Target of rapamycin complex 1 (TORC1)
We suspected that phosphatase 2A (PP2A) (Pph21 and Pph22), protein phosphatase 4 (PP4) (Pph3) and/or protein phosphatase 6 (PP6) (Sit4) might be involved in autophagy induction upon inactivation of TORC1, because these are negatively regulated by TORC1 [9]
Summary
Autophagy (or macroautophagy) degrades cytoplasmic components in lysosomes/vacuoles, which is a conserved system from the yeast to mammalian cells [1, 2]. Generated cupshaped structures, called isolation membranes, expand to encapsulate cellular cargos and the edges of isolation membranes fuse to form double membrane-surrounded autophagosomes. Autophagosomes fuse with lysosomes/vacuoles, and the engulfed cargoes are digested by lysosomal hydrolytic enzymes. In response to nutrient starvation, autophagy is dramatically induced to recycle proteins and other cellular components. Target of rapamycin complex 1 (TORC1), a nutrient-responsive protein kinase, regulates autophagy induction [3]. TORC1 phosphorylates Atg under nutrient-sufficient conditions, but TORC1 is inactivated under nutrient-starved conditions or by the specific TORC1 inhibitor rapamycin, which causes Atg dephosphorylation [4]
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