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.
|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|
|Wang, Tao; Darwin, K Heran; Li, Huilin (2010) Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation. Nat Struct Mol Biol 17:1352-7|
|Li, Dongyang; Li, Hua; Wang, Tao et al. (2010) Structural basis for the assembly and gate closure mechanisms of the Mycobacterium tuberculosis 20S proteasome. EMBO J 29:2037-47|
|Lin, Gang; Li, Dongyang; Chidawanyika, Tamutenda et al. (2010) Fellutamide B is a potent inhibitor of the Mycobacterium tuberculosis proteasome. Arch Biochem Biophys 501:214-20|
|Wang, Tao; Li, Hua; Lin, Gang et al. (2009) Structural insights on the Mycobacterium tuberculosis proteasomal ATPase Mpa. Structure 17:1377-85|
|Lin, Gang; Li, Dongyang; de Carvalho, Luiz Pedro Sorio et al. (2009) Inhibitors selective for mycobacterial versus human proteasomes. Nature 461:621-6|
|Li, Huilin; Thanassi, David G (2009) Use of a combined cryo-EM and X-ray crystallography approach to reveal molecular details of bacterial pilus assembly by the chaperone/usher pathway. Curr Opin Microbiol 12:326-32|