Unlike eukaryotes, most bacteria do not have a proteasome, but instead, use other protease complexes such as ClpAP and HslUV for their ATP-dependent proteolysis needs. In Mycobacterium tuberculosis (Mtb), however, proteasome is not only present, but its activity is essential for the pathogen to persist in the macrophages o mammalian lung epithelium. Recent research has firmly established that the mycobacterial proteasome is a druggable target and that inhibiting its activity could kill the bacteria. Surprisingly, Mtb uses a ubiquitin (Ub)-like tag, the prokaryotic ubiquitin-like protein (Pup), for delivering the doomed protein for proteasomal degradation. Despite functional similarities between Pup and Ub systems, recent work has revealed fundamental differences between these two conjugation pathways, and between Ub and Pup themselves. Therefore, the prokaryotes and eukaryotes have developed parallel but distinct mechanisms to regulate the protein stability by proteasomes. During the previous funding period, we have successfully addressed several important questions centered on the Mtb 20S proteasome assembly, gate closure and opening mechanism, and how the proteolytic activity is inhibited by the general or Mtb-specific proteasomal inhibitors. We have also revealed that the proteasomal ATPase Mpa recognizes and recruits the pupylated protein substrates via a binding-induced folding mechanism. In the next funding cycle, we will continue to study Mtb proteasome inhibition by novel compounds, and to understand structure and function of the Mtb Pup-proteasome pathway.
Mycobacterium tuberculosis (Mtb) is the causative agent for TB. The biological pathway Pup- proteasome is essential for Mtb to resist killing by the mammalian host macrophage. Our research on Mtb Pup-proteasome pathway will improve our knowledge on the unique system and facilitate anti-TB drug development.
|Bai, Lin; Hu, Kuan; Wang, Tong et al. (2016) Structural analysis of the dodecameric proteasome activator PafE in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 113:E1983-92|
|Jastrab, Jordan B; Wang, Tong; Murphy, J Patrick et al. (2015) An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 112:E1763-72|
|Tian, Ye; Wang, Tong; Liu, Wenyan et al. (2015) Prescribed nanoparticle cluster architectures and low-dimensional arrays built using octahedral DNA origami frames. Nat Nanotechnol 10:637-44|
|Burgie, E Sethe; Wang, Tong; Bussell, Adam N et al. (2014) Crystallographic and electron microscopic analyses of a bacterial phytochrome reveal local and global rearrangements during photoconversion. J Biol Chem 289:24573-87|
|Sun, Jingchuan; Evrin, Cecile; Samel, Stefan A et al. (2013) Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA. Nat Struct Mol Biol 20:944-51|
|Rath, Poonam; Huang, Chengdong; Wang, Tao et al. (2013) Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 110:E4790-7|
|Samanovic, Marie I; Li, Huilin; Darwin, K Heran (2013) The pup-proteasome system of Mycobacterium tuberculosis. Subcell Biochem 66:267-95|
|Yang, Shaoqing; Wang, Tao; Bohon, Jen et al. (2012) Crystal structure of the coat protein of the flexible filamentous papaya mosaic virus. J Mol Biol 422:263-73|
|Burns, Kristin E; Cerda-Maira, Francisca A; Wang, Tao et al. (2010) "Depupylation" of prokaryotic ubiquitin-like protein from mycobacterial proteasome substrates. Mol Cell 39:821-7|
|Qi, Shiqian; Pang, Yuxuan; Hu, Qi et al. (2010) Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4. Cell 141:446-57|
Showing the most recent 10 out of 16 publications