Cdk1/Cdc28-Dependent Activation of the Major Triacylglycerol Lipase Tgl4 in Yeast Links Lipolysis to Cell-Cycle Progression

Abstract

Triacylglycerols (TGs) serve essential cellular functions as reservoirs for energy substrates (fatty acids) and membrane lipid precursors (diacylglycerols and fatty acids). Here we show that the major yeast TG lipase Tgl4, the functional ortholog of murine adipose TG lipase ATGL, is phosphorylated and activated by cyclin-dependent kinase 1 (Cdk1/Cdc28). Phospho-Tgl4-catalyzed lipolysis contributes to early bud formation in late G1 phase of the cell cycle. Conversely, lack of lipolysis delays bud formation and cell-cycle progression. In the absence of beta-oxidation, lipolysis-derived metabolites are thus required to support cellular growth. TG homeostasis is the only metabolic process identified as yet that is directly regulated by Cdk1/Cdc28-dependent phosphorylation of key anabolic and catabolic enzymes, highlighting the importance of FA storage and mobilization during the cell cycle. Our data provide evidence for a direct link between cell-cycle-regulatory kinases and TG degradation and suggest a general mechanism for coordinating membrane synthesis with cell-cycle progression.

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

“…This cell-cycle delay is also reflected in the timing of the onset of bud formation (Fig. 1B), consistent with previous results (6). However, there was no general defect in cell growth during the log phase, and all mutants essentially reached the same cell density in the stationary phase (Fig.…”

“…Previous work from our laboratory has demonstrated a requirement of lipolysis for efficient cell-cycle progression (6). Absence of the major TG lipases Tgl3 and Tgl4 extends the G1/S transition of the cell cycle by ∼30 min in RediGrad-synchronized G0 cells (Fig.…”

“…Kurat et al showed that Tgl4, next to Tgl3, one of the two major TG lipases in yeast and the ortholog of mammalian ATGL (4,5), is also phosphorylated by Cdc28. In contrast to Pah1, however, Tgl4 is activated by Cdc28 (6). This inverse regulation of Pah1 and Tgl4 by Cdc28-dependent phosphorylation led to the model by which the TG content oscillates during the cell cycle: On the one hand, TG synthesis serves as a buffer for excess de novo generated fatty acids (FAs), and on the other hand, in times of increased demand-that is, at the onset of bud formation and bud growth-Tgl4-catalyzed lipolysis becomes active to provide TG-derived precursors for membrane lipid synthesis (6).…”

“…As a consequence of defective lipolysis, entry of quiescent cells into vegetative growth is significantly delayed; thus, TG breakdown is particularly important for promoting exit from the stationary phase and entry into the gap1 (G1) phase of the cell cycle (4,6,19).…”

Not Just Fat: The Structure and Function of the Lipid Droplet

“…Functionally we would like to know why fatty acids generated in LDs are used more effectively than those from other sources in many reactions (Gibbons et al 2000;Kurat et al 2009;Chandak et al 2010;Gruber et al 2010). The difference may be attributed to other metabolites made in LDs and/or the dynamic hydrolysis-reacylation cycle in LDs.…”