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Tuberculosis, one of the leading causes of death in the world, results from infection with Mycobacterium tuberculosis (Mtb). Current therapies consist of a daily regime of multiple antibiotics over a period of several months. Side effects and problems with efficacy have resulted in the prevalence of multi-drug resistant strains of Mtb. New therapies that reduce treatment time and toxicity are critical to control the spread of this disease.
Mtb contains the Pup-proteasome pathway (PPS), where post-translational modification with Pup (prokaryotic ubiquitin-like protein) serves as a signal for degradation by the Mpa-proteasome complex. In this pathway, Pup is first activated by Dop (deamidase of Pup) by deamidation at the carboxyl-terminal glutamine residue, converting it to glutamate. PafA (proteasome accessory factor A) catalyzes the ligation of the glutamyl side-chain of Pup to a lysine residue of a target protein, forming an iso-peptide bond. Pup-linked substrates are guided to the proteasome through Pup’s association with Mpa (mycobacterium proteasomal ATPase). Mpa recognizes and unfolds pupylated proteins, delivering them to the proteasome for degradation. Dop can also function as a depupylase to reverse the Pup modification prior to degradation. Each of these five proteins appears to be required for a functional PPS in mycobacteria.
The PPS is critical for Mtb to cause lethal infections in vivo and at least three proteins in this pathway are unique to bacteria, providing ideal targets for the development of chemotherapies against Mtb. I will discuss recent developments in the characterization of the Pup pathway and its affects on tuberculosis pathogenesis.