Research Topic: Yeast and mammalian cell biology; progeria and lamin A processing; ER quality control and cystic fibrosis, ABC transporters

The overall goal of our research is to dissect fundamental cellular processes relevant to human health and disease, using yeast and mammalian cell biology, biochemistry, and high-throughput genomic approaches. One project in the laboratory focuses on a premature aging disorder, Hutchinson-Gilford progeria syndrome (HGPS), which results from a mutation in the gene encoding the nuclear scaffold protein lamin A.  Children with HGPS exhibit profound characteristic of aging, including hair loss, skin and bone defects, and heart disease.  The mutant form of lamin A in HGPS patient cells is persistently modified by the lipid farnesyl (an aberrant situation, since normally a proteolytic cleavage removes the farnesylated C-terminal tail of lamin A during biogenesis).  Excitingly, we have found that a particular class of anti-cancer drugs called the farnesyl transferase inhibitors (FTIs) can dramatically block the nuclear abnormalities characteristic of HGPS fibroblasts and thus may be useful to treat HGPS.  We are currently examining the basic cell biology of lamin A processing, molecular mechanisms of lamin A toxicity in HGPS, and the link between HGPS and normal aging.

Another project in our laboratory focuses on ER quality control (ERQC), a process which ensures that misfolded secretory and membrane proteins, such as the mutant cystic fibrosis channel protein, are retained in the endoplasmic reticulum and subsequently undergo degradation by the ubiquitin-proteasome system.  Our goal is to identify the core cellular machinery that mediates ERQC.  To do so, we are using misfolded proteins as 'bait' in a variety of genome-wide yeast screens designed to uncover the eukaryotic ERQC machinery.  Ultimately, a detailed understanding of the cellular players that mediate this process will facilitate development of treatments for ERQC-based diseases such as cystic fibrosis.

Selected Publications

Barrowman, J., and Michaelis, S. (2009)  ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders. Biological Chemistry (In press)

Metzger MB, and Michaelis S. (2009) Analysis of Quality Control Substrates in Distinct Cellular Compartments Reveals a Unique Role for Rpn4p in Tolerating Misfolded Membrane Proteins.  Mol. Biol. Cell 20:1006-1019

Nakatsukasa, K., Huyer, G., Michaelis, S., and Brodsky J. L.  (2008) Dissecting the ER-Associated Degradation of a Misfolded Polytopic Membrane Protein. Cell 132: 101-112

Hudon, S. E., Coffinier, C., Michaelis, S., Fong, L. G., Young, S. G., and Hrycyna, C. A.  (2008)  HIV-Protease inhibitors block the enzymatic activity of purified Ste24p.  Biochem Biophys Res Comm. 374:365-368

Paumi, C. M., Chuk, M., Chevelev I., Stagljar, I., and Michaelis S. (2008) Negative regulation of the yeast ABC transporter Ycf1p by phosphorylation within its N-terminal extension. J. Biol. Chem.  283:27079-27088

Metzger, M. B. Maurer, M. J., Dancy, B. M., and Michaelis, S. (2008) Degradation of a cytosolic protein requires ER-associated degradation (ERAD) machinery. J. Biol. Chem. 283:32302-32316

Barrowman, J., Hamblet, C., George, C.M., and Michaelis, S. (2008) Analysis of prelamin A biogenesis reveals the nucleus to be a CaaX processing compartment.  Mol. Biol. Cell 12:5398-5408

Paumi, C. M., Menendez, J., Arnoldo, A, Engels, K, Iyer, K. R., Thaminy, S, Georgiev, O., Barral Y., Michaelis, S, and Stagljar, I. (2007) Mapping Protein-Protein Interactions for the Yeast ABC Transporter Ycf1p by Integrated Split-Ubiquitin Membrane Yeast Two-Hybrid (iMYTH) Analysis.  Molecular Cell 26: 15-25.

Huyer, G., Kistler, A., Nouvet, F. J., George, C., Boyle, M. L., and Michaelis, S.  (2006) Saccharomyces cerevisiae a-factor mutants reveal residues critical for processing, activity, and export.  Eukaryotic Cell 5: 1560-1570.

Gelb, M. H., Brunsveld, L., Hrycyna, C. A., Michaelis, S., Tamanoi, F., Van Voorhis, W. C., and Waldmann, H. (2006) Therapeutic intervention based on protein prenylation and associated modifications. Nature Chemical Biology 2:518-528.

Mallampalli, M. P., Huyer, G., Bendale, P., Gelb, M. H., and Michaelis, S. (2005) Inhibiting Farnesylation Reverses the Nuclear Morphology Defect in a HeLa Cell Model for Hutchinson-Gilford Progeria Syndrome, Proc Natl. Acad Sci. USA 102:14416-14421.

Young, S. G. Fong, L., and Michaelis, S.  (2005) Prelamin A, Zmpste24, misshapen cell nuclei, and progeria- new evidence suggesting that protein farnesylation could be important for disease pathogenesis.  Journal of Lipid Research 46:2531-2558.

Anderson, J. L., Frase, H., Michaelis, S., and Hrycyna, C. A.  (2005)  Purification, functional reconstitution and characterization of the Saccharomyces cerevisiae isoprenylcysteine carboxyl methyltransferase Ste14p. J. Biol. Chem. 280:7336-7345.

Huyer, G., Piluek, W. F., Fansler, Z., Kreft, S. K., Hochstrasser, M, Brodsky, J. L. and Michaelis, S.  (2004) Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble lumenal protein. J. Biol. Chem.  279:38369-38378.

Huyer, G. ,  Longsworth G. L., Mason, D. L., Mallampalli, M. P. McCaffery, J. M., Wright, R.. L., and Michaelis, S. (2004) A novel quality control subcompartment in Saccharomyces cerevisiae: The endoplasmic reticulum-associated compartment (ERAC), Mol. Biol. Cell 15: 908-921.