K. Heran Darwin

Dr. Darwin's research focuses on understanding how a protein degradation system called the proteasome contributes to the pathogenesis of Mycobacterium tuberculosis (Mtb). ATP-dependent proteolysis by the Mtb proteasome requires a 20S proteasome core particle and Pup (prokaryotic ubiquitin-like protein), the first post-translational, protein-on-protein modifier identified in prokaryotes, which targets numerous proteins for degradation. Dr. Darwin's lab also found a second proteasome activator, PafE, that degrades specific proteins without ATP. Her group further determined ATP-dependent and -independent proteasome activities degrade transcriptional repressors of two essential protein quality controls systems, demonstrating a crucial role of proteasome function in Mtb. How these repressors and other substrates are selected for degradation is an active area of investigation. In addition to degrading transcriptional regulators, the failed degradation of a specific enzyme, a cytokinin synthase called Log, results in aldehyde accumulation that sensitizes Mtb to nitric oxide and copper. This work has inspired new lines of investigation about the role of aldehyde metabolism in both host and microbe, and how it might contribute to pathogen control.