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Date of Award
Sensing and responding to environmental changes is an important aspect of mycobacterial physiology. Mycobacterium tuberculosis comprises eleven eukaryotic-type Ser/Thr protein kinases as well as other signaling components. Our lab reported that the PknA and the PknB kinases are involved in the regulation of cell division of M. tuberculosis. One substrate of PknA/B we identified is Wag31, whose phosphorylation plays an important role in regulating cell growth by controlling polar peptidoglycan biosynthesis. We recently identified two additional substrates of PknA and PknB: the α-subunit (PrcA) and the β-subunit (PrcB) of the proteasome, which is required for persistence of M. tuberculosis during the chronic phase of infected mice. While the proteasome appears to be important in persistence by countering the destructive effects of toxic nitrogen compounds produced in the macrophage, the molecular mechanisms by which the proteasome controls these processes remain largely unknown. Here, I show that the α-subunit of proteasome is phosphorylated by PknB both in vitro and in vivo. I also show that three Thr residues in PrcA are phosphorylated by PknB in a sequential manner. Finally, I demonstrate that the phosphorylation of PrcA in the proteasome may regulate substrate degradation in vivo in mycobacterial cells. This research is significant because it may provide an insight into how M. tuberculosis coordinates its cellular processes by regulating the phosphorylation status of the proteasomal subunits. Since the absence of PknA/B or proteasome leads to complete or dramatic inhibition of M. tuberculosis growth, this study may also provide a new therapeutic strategy to treat tuberculosis by targeting these proteins.
Han, Jaeil, "The role of proteasome phosphorylation in mycobacterium tuberculosis" (2011). Wayne State University Theses. 143.