Susan Michaelis
Johns Hopkins University, MD·Biochemistry
Cells build many of their proteins as precursors that must be trimmed before they work. One such precursor, prelamin A, carries a greasy chemical tag called a farnesyl group that helps it reach the membrane surrounding the nucleus; an enzyme then cuts off the tagged end to make mature lamin A, part of the scaffold that gives the nucleus its shape.
- Fields
Biochemistry
Genetics
Microbiology & Immunology
- Topics
prelamin A
farnesylation
progeria
- Grants
- 2 known grants, through Apr 2028
What they work on
- Determine how accumulation of farnesylated prelamin A affects bone, by measuring the number, function, development, transcriptomes, and signaling of bone cells in LmnaL648R/L648R mice, which cannot process prelamin A, and comparing with normal aging mice.
- Test whether prelamin A accumulation causes vascular disease, by following LmnaL648R/L648R mice as they age and by crossing them to Ldlr-knockout mice with high-fat diet to sensitize them to atherosclerosis.
- Define the earliest cellular events caused by prelamin A using time-course transcriptomic analysis in cultured cells, and test whether prelamin A ruptures the nuclear envelope so that DNA triggers a cytosolic sensor and an inflammatory gene program.
- Test whether prelamin A actually accumulates during normal aging, by probing bone and vascular tissue from young and old mice, human tissue arrays, and fibroblasts from young and aged individuals.
- Determine which step of membrane protein biogenesis, insertion, topology, stability and quality control, modification, or oligomerization, the zinc metalloprotease ZMPSTE24 controls, using IFITM3 as its candidate substrate in the endoplasmic reticulum.
- Test the alternative that ZMPSTE24 assists IFITM3's membrane-rigidifying, fusion-blocking activity indirectly, by being recruited to IFITM3 or by altering the composition, properties, or fluidity of the lipid bilayer.
More about the research
When that cut fails, the tagged precursor builds up and people develop premature aging diseases. Two projects follow this biology in different directions: one asks how the uncut precursor damages bone and blood vessels and whether it also accumulates in ordinary aging, the other asks what else the cutting enzyme does, including an unexpected role in defending cells against viruses.
Why it matters
Children with progeria and related disorders accumulate prelamin A and suffer bone loss and cardiovascular disease; showing how the protein damages bone and vessel cells could change how these diseases are treated. If prelamin A also builds up during ordinary aging, it becomes a candidate target for age-associated osteoporosis and cardiovascular disease. Separately, understanding how ZMPSTE24 enables IFITM3 to block virus-cell fusion, the first step of infection by many enveloped viruses, may eventually be harnessed for antiviral drug development.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Rebecca Delventhal
Lake Forest College, IL·Biology
Determine whether glial EMC4, a subunit of the ER membrane protein complex, is required during development or for maintenance of the adult fly, by timing RNAi knockdown across life stages in Drosophila.
Bo Wang
University of Illinois Urbana-Champaign, IL·Physiology
Examine how SEC16B, a scaffold protein on the endoplasmic reticulum, regulates the formation of lipid droplets (fat-storage bodies) in liver cells, using cell-culture and in vivo experiments.
Malavika Raman
Tufts University, MA·Biochemistry
Identify how UBXN1 represses translation (protein synthesis at the ribosome), testing whether it binds specific ribosomal proteins in a ubiquitin-dependent way.
The school
Johns Hopkins University: 100 labs on PI Pages, $4.1B a year on research, 622 research doctorates a year.
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