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The premature aging disease progeria and lamin A processing; ubiquitin-proteasome mediated protein quality control.
We study fundamental cellular processes relevant to human disease. A major research focus in our laboratory is the premature aging disease 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, mechanistic features of the ZMPSTE24 membrane protease, 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 require a detailed understanding of the cellular protein quality control machinery.
Ast, T., Michaelis, S., Schuldiner, M. (2016) The protease Ste24 clears clogged translocons. Cell 164:103-114 PMC4715265
Maurer, M.J., Spear, E.D., Yu, A.T., Lee, E.J., Shahzad, S, and Michaelis, S. (2016) Degradation signals for ubiquitin-proteasome dependent cytosolic protein quality control (CytoQC) in yeast. (2016) G3:Genes, Genomes, Genetics 6:1853-66, PMC4938640
Kane, M. S., Linsday, 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 A 161:1599-1611 PMCID: PMC3740161
Michaelis, S. and Hrycyna, C.A. (2013) A protease for the ages. Science 339:1529-30. PMID: 23539586
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. PMC3429625
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. PMC3428156
Barrowman, J., Hamblet, C., Kane M.S., Michaelis, S. (2012) Requirements for efficient protelolytic cleavage of prelamin A by ZMPSTE24. PLoS ONE 7: e32120. PMC3280227
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. PMC2633399
Barrowman, J., and Michaelis, S. (2009) ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders. Biological Chemistry 390: 761-773. PMID: 19453269
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. PMC2592638
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. PMC2543933
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. PMID: 17434123*Denotes 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. PMC1242289