title: Fission Yeast SCYL1/2 Homologue Ppk32: A Novel Regulator of TOR Signalling That Governs Survival during Brefeldin A Induced Stress to Protein Trafficking.
abstract: Target of Rapamycin (TOR) signalling allows eukaryotic cells to adjust cell growth in response to changes in their nutritional and environmental context. The two distinct TOR complexes (TORC1/2) localise to the cell's internal membrane compartments; the endoplasmic reticulum (ER), Golgi apparatus and lysosomes/vacuoles. Here, we show that Ppk32, a SCYL family pseudo-kinase, is a novel regulator of TOR signalling. The absence of ppk32 expression confers resistance to TOR inhibition. Ppk32 inhibition of TORC1 is critical for cell survival following Brefeldin A (BFA) induced stress. Treatment of wild type cells with either the TORC1 specific inhibitor rapamycin or the general TOR inhibitor Torin1 confirmed that a reduction in TORC1 activity promoted recovery from BFA induced stress. Phosphorylation of Ppk32 on two residues that are conserved within the SCYL pseudo-kinase family are required for this TOR inhibition. Phosphorylation on these sites controls Ppk32 protein levels and sensitivity to BFA. BFA induced ER stress does not account for the response to BFA that we report here, however BFA is also known to induce Golgi stress and impair traffic to lysosomes. In summary, Ppk32 reduce TOR signalling in response to BFA induced stress to support cell survival.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Katarzyna M
authors.identifier: 0000-0003-2349-7534
authors.initials: KM
authors.lastname: Kowalczyk
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.|Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia.|South Australia Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Janni
authors.initials: J
authors.lastname: Petersen
mesh_terms: D020126:Brefeldin A / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000235:genetics; D008247:Lysosomes / Q000187:drug effects / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics*; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics*; D012568:Schizosaccharomyces / Q000235:genetics / Q000254:growth & development; D020123:Sirolimus / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014617:Vacuoles / Q000187:drug effects / Q000235:genetics
chemical_list: D046912:Multiprotein Complexes; D020126:Brefeldin A; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus