Identification of a proteolysis regulator for an essential enzyme inMycobacterium tuberculosis

Abstract

AbstractInMycobacterium tuberculosisproteins that are post-translationally modified with Pup, a prokaryotic ubiquitin-like protein, can be degraded by proteasomes. While pupylation is reversible, mechanisms regulating substrate specificity have not been identified. Here, we identify the first depupylation regulators: CoaX, a pseudokinase, and pantothenate, an essential, central metabolite. In a ΔcoaXmutant, pantothenate synthesis enzymes were more abundant, including PanB, a substrate of the Pup-proteasome system. Media supplementation with pantothenate decreased PanB levels in acoaXand Pup-proteasome-dependent manner.In vitro, CoaX accelerated depupylation of Pup∼PanB, while addition of pantothenate inhibited this reaction. Collectively, we propose CoaX contributes to proteasomal degradation of PanB by modulating depupylation of Pup∼PanB in response to pantothenate levels.One Sentence SummaryA pseudo-pantothenate kinase regulates proteasomal degradation of a pantothenate synthesis enzyme inM. tuberculosis.