|Department Affiliations||Department of Cell Biology|
|SOM Address||106 Biophysics Building|
Progeria and lamin A processing; ERAD and cytosolic protein quality control mediated by the ubiquitin-proteasome system; yeast and mammalian cell biology.
We study fundamental cellular processes relevant to human disease. A major focus or research in our laboratory is on the 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 characteristics 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 cleavage by the ZMPSTE24 protease removes the farnesylated C-terminal tail of lamin A during biogenesis. We are examining the cell biology of lamin A processing, the molecular mechanisms of lamin A toxicity in HGPS, therapeutic strategies, and the link between HGPS and normal aging.
We also study protein quality control mediated by the ubiquitin-proteasome system. Misfolded secretory and membrane proteins are efficiently degraded by ER-associated degradation (ERAD), while cytosolic quality control (CytoQC) pathways handle misfolded soluble proteins. Our goal is to identify the core cellular machinery involved in recognition of misfolded proteins, using model proteins as ‘bait’ in genome-wide yeast screens designed to uncover the eukaryotic ERAD and CytoQC machinery. Ultimately, devising treatment for protein misfolding diseases such as cystic fibrosis or Parkinson’s will rely on a detailed understanding of cellular protein quality control machinery.
- Michaelis, S. and Hrycyna, C.A. (2013) A protease for the ages. Science 339:1529-30.
- Kane, M. S., Lindsay, M. E., Judge, D. P., Barrowman, J., Ap Rys, C., Simonson, L., Dietz, H.C., Michaelis, S. (2013) LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset. American Journal of Medical Genetics, Part A (In Press).
- Barrowman J., Wiley, P.A., Hudon, S., Hrycyna, C.A. Michaelis, S. (2012) Human ZMPSTE24 disease mutations: residual enzymatic activity correlates with disease severity. Human Molecular Genetics 21:4084-4093.
- Barrowman, J., Hamblet, C., Kane M.S., Michaelis, S. (2012) Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24. PLoS ONE 7: e32120.
- Michaelis, S. and Barrowman, J. Biogenesis of the Saccharomyces cerevisiae pheromome a-factor; from yeast mating to human disease. (2012) Microbiology and Molecular Biology Reviews 76: 626-651.
- 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
- Barrowman, J., and Michaelis, S. (2009) ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders. Biological Chemistry 390: 761-773.
- 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.
- 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
- 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
- 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. * Co-corresponding senior authors.
- 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.