The research in Susan Henry’s laboratory focuses on regulation of membrane lipid metabolism in yeast and its coordination with membrane trafficking and signal transduction (Gaspar et al., 2006b; Jesch and Henry, 2005; Nunez and Henry, 2005). Most recently, we have shown that signals arising from lipid metabolism in the endoplasmic reticulum (ER) influence major transcriptional networks in the cell (Gaspar et al., 2006a; Jesch et al., 2006; Jesch et al., 2005; Loewen et al., 2004). This metabolism influences, and is influenced by, several major signal transduction pathways including the unfolded protein response pathway (Chang et al., 2004; Chang et al., 2002) and the protein-kinase (PKC) pathway (Sreenivas et al., 2001 Nunez, 2006;) and the glucose response pathway (Shirra et al., 2001).

Our most recent work has focused on the relationship of transcriptional and metabolic responses following the introduction of the phospholipid precursor, inositol, into the growth medium of actively-dividing yeast cells. The transcription patterns of over 700 genes are altered within two hours (equivalent to about one doubling time) following introduction of inositol. Statistical analysis identified at least six distinct expression responses (Jesch et al., 2006) including repression of phospholipid biosynthetic genes regulated by Opi1p, as well as genes regulated by the UPR pathway and transient induction of lipid remodeling genes regulated by Mga2p. These three categories of genes are known to respond to signals arising in the ER and the kinetics of the changes in their transcript abundance were rapid, occurring within the first 15 to 30 minutes following introduction of inositol. Analysis of changes in lipid metabolism over the same time frame revealed rapid consumption of phosphatidic acid (PA) which was shown to interact with Opi1p and to be required for its retention in the ER (Loewen et al., 2004). Consumption of PA results in translocation of Opi1p to the nucleus and repression of phospholipid biosynthetic genes including INO1. At the same time, the rate of synthesis of phosphatidylinositol (PI) and the rate of phosphatidylcholine (PC) turnover both increase dramatically (Gaspar et al., 2006a; Loewen et al., 2004). These changes all occur within 15 to 30 minutes following the introduction of inositol to the growth medium (Gaspar et al., 2006a). When choline is present in the medium, the acyl chain composition of PC is also rapidly remodeled in response to inositol turnover and remodeling of PC in response to inositol addition was shown to be dependent upon the activity of Nte1p (Gaspar et al., 2006a), a phospholipase B located in the ER. Thus, addition of inositol produces rapid remodeling of cellular phospholipid content and simultaneous triggers multiple ER to nucleus signaling pathways.

Ongoing research in our laboratory focuses on understanding the nature of metabolic signals triggered by changes in lipid metabolism and their interaction with major cellular signal transduction pathways and transcriptional networks in the cell.

PUBLICATIONS 2001-PRESENT

A. Sreenivas, M. J. Villa-Garcia, S. A. Henry, and G. M. Carman. 2001. Phosphorylation of the Yeast Phospholipid Synthesis Regulatory Protein Opi1p by Protein Kinase C. J. Biol. Chem., 276: 29915-29923.

M. K. Shirra, J. Patton-Vogt, A. Ulrich, O. Liuta-Tehlivets, S. D. Kohlwein, S. A. Henry and K. M. Arndt. 2001. Inhibition of Acetyl-CoA Carboxylase Activity Restores Expression of the INO1 Gene in a snf1 Mutant Strain of Saccharomyces cerevisiae. Mol. Cell. Biol., 21: 5710-5722.

H. J. Chang, E. W. Jones, and S. A. Henry. 2002. Role of the Unfolded Protein Response Pathway in Regulation of INO1 and in the sec14 Bypass Mechanism in Saccharomyces cerevisiae. Genetics, 162: 29-43.

C.J.R. Loewen, M. L. Gaspar, S. A. Jesch, C. Delon, N. T. Ktistakis, S. A. Henry, and T. P. Levine. 2004. Phospholipid Metabolism Regulated by a Transcription Factor Sensing Phosphatidic Acid. Science, 304: 1644-1647.

H. J. Chang, S. A. Jesch, M. L. Gaspar, and S. A. Henry. 2004. Role of the Unfolded Protein Response Pathway in Secretory Stress and Regulation of INO1 Expression in Saccharomyces cerevisiae. Genetics, 168: 1899-1913.

S. A. Jesch, X. Zhao, M. T. Wells, and S. A. Henry. 2005. Genome Wide Analysis Reveals Inositol, Not Choline, as the Major Effector of Ino2p-Ino4p and Unfolded Protein Response Target Gene Expression in Yeast. J. Biol. Chem., 280: 9106-9118. Supplemental Data ReadMe

L. R. Nunez and S. A. Henry. 2005. Regulation of 1D-myo-inositol-3-phosphate Synthase in Yeast. In: Subcellular Biochemistry: Biology of Inositols and Phosphoinositides, Ed. A. L. Majumder and B. B. Biswas, Kluwer Academic/Plenum Publishers, London, UK, Vol. 39: 135-156.

S. A. Jesch and S. A. Henry. 2005. Yeast Inositol Lipids: Synthesis, Regulation, and Involvement in Membrane Trafficking and Lipid Signaling. In: Cell Biology and Dynamics of Yeast Lipids, G. Daum (Ed.). Research Signpost, Kerala, India, Vol: 37/661: 105-131.

H. A. Boumann, J. Gubbens, M. C. Koorengevel, C. S. Oh, C. E. Martin, A. J. Heck, J. Patton-Vogt, S. A. Henry, B. de Kruijff, and A. I. de Kroon. 2006. Depletion of Phosphatidylcholine in Yeast Induces Shortening and Increased Saturation of the Lipid Acyl Chains: Evidence for Regulation of Intrinsic Membrane Curvature in a Eukaryote. Mol Biol Cell, 17:1006-1017.

M. L. Gaspar, M. A. Aregullin, S. A. Jesch, and S. A. Henry. 2006a. Inositol Induces a Profound Alteration in the Pattern and Rate of Synthesis and Turnover of Membrane Lipids in Saccharomyces cerevisiae. J. Biol. Chem., 281: 22773-22785.

S. A. Jesch, P. Liu, X. Zhao, M. T. Wells, and S. A. Henry. 2006. Multiple endoplasmic reticulum-to-nucleus signaling pathways coordinate phospholipid metabolism with gene expression by distinct mechanisms. J. Biol. Chem., 281: 24070-24083. Supplemental Data ReadMe

M. L. Gaspar, M. A. Aregullin, S. A. Jesch, L. R. Nunez, M. Villa-Garcia, and S. A. Henry. 2006b. The emergence of yeast lipidomics. In: Regulation of Lipid Metabolism in Yeast, G. Carman and S. A. Henry (Ed.). Biochimica et Biophysica Acta, in press.

Nunez, L. 2006. Phospholipid biosynthesis in yeast: The role of the PKC1-MPK1 signal transduction pathway, Ph.D. Thesis, Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY.