Susan Doris Michaelis, PhD

Primary Academic Title

Professor of Cell Biology

Background

Centers and Institutes

• Basic Biomedical Sciences, Institute for
• McKusick-Nathans Institute of Genetic Medicine

Additional Academic Titles

Professor of Genetic Medicine

Research Interests

ABC transporters, Cytosolic protein quality control, Endocytosis, ER quality control, ERAD, Hutchinson-Gilford progeria syndrome (HGPS or progeria), Lamin A, Mammalian cell biology, Yeast protein trafficking and human disease, ZMPSTE24 protease

Lab Website

Susan Michaelis Lab

• The Michaelis Laboratory's research goal is to dissect fundamental cellular processes relevant to human health and disease, using yeast and mammalian cell biology, biochemistry and high-throughput genomic approaches. Our team studies the cell biology of lamin A and its role in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Other research focuses on the core cellular machinery involved in recognition of misfolded proteins. Understanding cellular protein quality control machinery will ultimately help researchers devise treatments for protein misfolding diseases in which degradation is too efficient or not enough.

Research Summary

The overarching goal of Dr. Michaelis’s 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 of her team’s focuses 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.

Dr. Michaelis and her group 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.

The team also studies 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.

Their research 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 in which degradation is too efficient (e.g. cystic fibrosis) or not efficient enough (e.g., neurological disorders like Parkinson’s) will rely on a detailed understanding of cellular protein quality control machinery.

Selected Publications

• Barrowman J, Hamblet C, Kane MS, Michaelis S. (2012) “Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24.” PLoS ONE 7: e32120.

• Barrowman J, Wiley PA, Hudon S, Hrycyna CA, Michaelis, S. (2012) “Human ZMPSTE24 disease mutations: residual enzymatic activity correlates with disease severity.” Human Molecular Genetics 21:4084-4093.

• Kane MS, Lindsay ME, Judge DP, Barrowman J, Ap Rys C, Simonson L, Dietz HC, 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).

• Michaelis S and Hrycyna CA. (2013) “A protease for the ages.” Science 339:1529-30

• 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.

Graduate Program Affiliations

• Biochemistry, Cellular and Molecular Biology

  Cellular and Molecular Medicine

  Human Genetics