Karla Satchell, PhD
Professor, Microbiology-Immunology; Feinberg School of Medicine
Research Program
Cancer-Focused Research
My interest in the mechanisms of action of bacterial protein toxins spans over 27 years. I first started working on RTX toxins in 1988 as a research tech in pharmacology shortly after earning my undergraduate degree. After two years focused on protein purification and toxic mechanisms, I went to graduate school and post-doctoral training focused on bacterial pathogenesis using genetic manipulation of bacteria as a primary tool. These approaches gave me a strong background for returning to toxin research combining biochemistry with genetics to study protein toxin function.
This project has been stimulated by 18 years of NIH-funded research on Multifunctional-Autoprocessing RTX (MARTX) toxins. These toxins are unique assemblages of multiple protein domain toxic to eukaryotic cells (known as "effector domains") arrayed into a >4500 aa polypeptides capable of delivering this "bolus" of toxicity across the plasma membrane to the cytoplasm of eukaryotic cells in a single step. My lab in the last 16 years has been the leader in discovery of these toxins, characterization of their ability to deliver cargo, and determining the mechanism of action of the various effector domains delivered. No other lab worldwide focuses exclusively on the mechanism of action of these toxins.
We recently discovered one of these effectors has a Ras/Rap1 specific endopeptidase (RRSP) activity. Our initial studies published in 2014 and 2015 show that this is a cytotoxic domain and detailed biochemically the mechanism of action. Through our association with the cancer center since 2015, we have delved more deeply into this protein and its potential to understand Ras-driven cancers. We solved the structure and determined its mechanism of action. I have now assembled team of collaborators to understand the mechanism of action of RRSP, including association with the NCI Ras Initiative. I also a translation team that will address targeting RRSP into tumors. Further, we plan in the next few years to use our work on linkage of RRSP to understanding and treating cancer to other unique effectors we have discovered linked to inhibition of autophagy, activation of apoptosis, and silencing of the inflammatory response.