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Vol. 18, Issue 10, 4180-4189, October 2007

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Protein Kinase A and Sch9 Cooperatively Regulate Induction of Autophagy in Saccharomyces cerevisiae

Tomohiro Yorimitsu^*, Shadia Zaman, James R. Broach, and Daniel J. Klionsky^*

*Life Sciences Institute and Departments of Molecular, Cellular, and Developmental Biology and Biological Chemistry, University of Michigan, Ann Arbor, MI 48109; and Department of Molecular Biology, Princeton University, Princeton, NJ 08544

Submitted May 23, 2007; Revised July 30, 2007; Accepted August 6, 2007
Monitoring Editor: Janet Shaw

Autophagy is a highly conserved, degradative process in eukaryotic cells. The rapamycin-sensitive Tor kinase complex 1 (TORC1) has a major role in regulating induction of autophagy; however, the regulatory mechanisms are not fully understood. Here, we find that the protein kinase A (PKA) and Sch9 signaling pathways regulate autophagy cooperatively in yeast. Autophagy is induced in cells when PKA and Sch9 are simultaneously inactivated. Mutant alleles of these kinases bearing a mutation that confers sensitivity to the ATP-analogue inhibitor C3-1'-naphthyl-methyl PP1 revealed that autophagy was induced independently of effects on Tor kinase. The PKA–Sch9-mediated autophagy depends on the autophagy-related 1 kinase complex, which is also essential for TORC1-regulated autophagy, the transcription factors Msn2/4, and the Rim15 kinase. The present results suggest that autophagy is controlled by the signals from at least three partly separate nutrient-sensing pathways that include PKA, Sch9, and TORC1.

Address correspondence to: Daniel J. Klionsky (klionsky{at}umich.edu)

Abbreviations used: 1NM-PP1, C3-1'-naphthyl-methyl PP1; Atg, autophagy-related; Atg8–PE, Atg8 conjugated to phosphatidylethanolamine; PAS, phagophore assembly site; PKA, protein kinase A; prApe1, precursor aminopeptidase I; TORC1, Tor complex 1.