Figure 8. TORC2-Ypk1 signaling globally activates sphingolipid synthesis, selectively directs flux toward ceramide metabolites, and prevents LCBP cross-talk to the autophagy pathway.
(A) Diagram of yeast de novo sphingolipid biosynthesis shown is derived from (Dickson, 2008). Enzymes are in ovals. Metabolites are in boxes. Increased color intensity indicates level of metabolite increase in response TORC2-Ypk1 activation. TORC2-Ypk1 signaling globally activates de novo sphingolipid biosynthesis via derepression of the SPT complex (Roelants et al., 2011; Berchtold et al., 2012; Sun et al., 2012), potentially increasing levels of all metabolites. However, Ypk1 also upregulates ceramide synthesis via phosphorylation of Lac1 and Lag1, thus primarily directing this increased flux towards ceramides and away from LCBs and LCBPs. (B) In the absence of Ypk1 mediated ceramide biosynthesis regulation, increased sphingolipid flux raises LCB and LCBP levels. This slows cell growth by activating autophagy. Thus, TORC2-Ypk1 signaling not only activates sphingolipid biosynthesis in response to stress, but also insulates this flux towards ceramides to prevent metabolite mediated crosstalk to the autophagy machinery.