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Vol. 19, Issue 11, 4785-4803, November 2008

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Trans-Golgi Network and Endosome Dynamics Connect Ceramide Homeostasis with Regulation of the Unfolded Protein Response and TOR Signaling in Yeast

Carl J. Mousley^*,, Kimberly Tyeryar^*,, Kristina E. Ile^*, Gabriel Schaaf^*, Renee L. Brost, Charles Boone, Xueli Guan, Markus R. Wenk, and Vytas A. Bankaitis^*

*Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7090; Banting and Best Department of Medical Research and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; and Departments of Biochemistry and Biological Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Submitted April 25, 2008; Revised July 22, 2008; Accepted August 20, 2008
Monitoring Editor: Akihiko Nakano

Synthetic genetic array analyses identify powerful genetic interactions between a thermosensitive allele (sec14-1^ts) of the structural gene for the major yeast phosphatidylinositol transfer protein (SEC14) and a structural gene deletion allele (tlg2) for the Tlg2 target membrane-soluble N-ethylmaleimide-sensitive factor attachment protein receptor. The data further demonstrate Sec14 is required for proper trans-Golgi network (TGN)/endosomal dynamics in yeast. Paradoxically, combinatorial depletion of Sec14 and Tlg2 activities elicits trafficking defects from the endoplasmic reticulum, and these defects are accompanied by compromise of the unfolded protein response (UPR). UPR failure occurs downstream of Hac1 mRNA splicing, and it is further accompanied by defects in TOR signaling. The data link TGN/endosomal dynamics with ceramide homeostasis, UPR activity, and TOR signaling in yeast, and they identify the Sit4 protein phosphatase as a primary conduit through which ceramides link to the UPR. We suggest combinatorial Sec14/Tlg2 dysfunction evokes inappropriate turnover of complex sphingolipids in endosomes. One result of this turnover is potentiation of ceramide-activated phosphatase-mediated down-regulation of the UPR. These results provide new insight into Sec14 function, and they emphasize the TGN/endosomal system as a central hub for homeostatic regulation in eukaryotes.

These authors contributed equally to this work.

Address correspondence to: Vytas A. Bankaitis (vytas{at}med.unc.edu)