Regulation of ceramide biosynthesis by TOR complex 2

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Biology

Background:

• Sphingolipids, including ceramides and long-chain bases (LCBs), are vital for cell growth and survival, playing critical signaling roles.
• The sphingolipid biosynthetic pathway involves conserved reactions forming key intermediates.
• Components of the target of rapamycin complex 2 (TORC2) are linked to sphingolipid biosynthesis in yeast, but the specific regulatory step is unclear.

Purpose of the Study:

• To elucidate the precise step in sphingolipid biosynthesis regulated by TORC2 in yeast.
• To investigate the role of TORC2 in de novo ceramide biosynthesis.
• To identify downstream effectors and interacting pathways involved in TORC2-mediated ceramide production.

Main Methods:

• Analysis of de novo ceramide biosynthesis in yeast cells deficient in TORC2 activity, both in vivo and in vitro.
• Investigation of the role of the AGC kinase Ypk2 in TORC2-regulated ceramide synthesis.
• Examination of the antagonistic effect of calcineurin on this pathway.

Main Results:

• Yeast cells lacking TORC2 activity exhibit impaired de novo ceramide biosynthesis.
• TORC2 regulates ceramide biosynthesis, at least partially, through activation of the Ypk2 kinase.
• The Ca2+/calmodulin-dependent phosphatase calcineurin antagonizes this TORC2-mediated step.
• Ypk2 activation is also independently influenced by LCBs, the direct precursors to ceramides.

Conclusions:

• TORC2 signaling is coupled with LCB levels to control Ypk2 activity, thereby regulating ceramide formation.
• This study proposes a model where TORC2 integrates upstream signals to fine-tune ceramide biosynthesis.
• The findings reveal a novel regulatory mechanism for ceramide production essential for cell homeostasis.