Ubiquitin-Like Protein Involved in the Proteasome Pathway of Mycobacterium tuberculosis

The protein modifier ubiquitin is a signal for proteasome-mediated degradation in eukaryotes. Proteasome- bearing prokaryotes have been thought to degrade proteins via a ubiquitinin-dependent pathway. We have identified a prokaryotic ubiquitin- like protein, Pup ( Rv2111c), which was specifically conjugated to proteasome substrates in the pathogen Mycobacterium tuberculosis. Pupylation occurred on lysines and required proteasome accessory factor A (PafA). In a pafA mutant, pupylated proteins were absent and substrates accumulated, thereby connecting pupylation with degradation. Although analogous to ubiquitylation, pupylation appears to proceed by a different chemistry. Thus, like eukaryotes, bacteria may use a small- protein modifier to control protein stability.