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The virulence regulator VirB from Shigella flexneri uses a CTPdependent switch mechanism to activate gene expression

ABSTRACT: The transcriptional antisilencer VirB acts as a master regulator of virulence gene expression in the human pathogen Shigella flexneri. It binds defined sequences (virS) upstream of VirB-dependent promoters and counteracts their silencing by the nucleoid-organizing protein H-NS. However, its precise mode of action remains unclear. Notably, VirB is not a classical transcription factor but related to DNA partitioning pro- teins of the ParB family, which have recently been recognized as DNA-sliding clamps using CTP binding and hydrolysis to control their DNA entry gate. Here, we show that VirB binds CTP, embraces DNA in a clamp-like fashion upon its CTP-dependent loading at virS sites and slides laterally on DNA after clamp closure. Mutations that prevent CTP binding block the loading of VirB clamps in vitro and the formation of VirB nucleoprotein complexes in vivo. Thus, VirB represents a CTP-dependent molecular switch that uses a loading-and-sliding mechanism to control transcription during bacterial pathogenesis.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Shigella Flexneri 5a

SUBMITTER: Timo Glatter

LAB HEAD: Timo Glatter

PROVIDER: PXD046358 | Pride | 2023-12-06

REPOSITORIES: Pride

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Project description:Metabolism is fundamental to life, all life activities are sustained through metabolism. Metabolic engineering, while modifying host endogenous metabolic network or introducing heterologous pathway for biotechnological applications, often results in unfitness and suboptimal characteristics, because of the lack of full knowledge on host metabolism. Adaptive laboratory evolution (ALE), harnessing the nature of life -- evolution, has become a potent approach in phenotype optimization, environmental adaptation, and cell biology study1–3. Through ALE, alternative pathways of β-alanine biosynthesis4, pyridoxal 5’-phosphate (PLP) biosynthesis5, isoleucine biosynthesis6, as well as ATP generation7 have been uncovered; E. coli aerobic citrate utilization8,9 and various synthetic C1-trophy10–14 have been realized. In this study, we describe E. coli recruits the same workforce, Sad, in evolution through various strategies, i.e., catalytic efficiency improvement, gene dose increase, and gene expression regulations, to overcome metabolic damages (Fig. 1). Sad, i.e. NAD(P)+-dependent succinate semialdehyde dehydrogenase (SSADH), is an aldehyde dehydrogenase (ALDH) family protein. Sad oxidizes succinate semialdehyde to succinate, preventing accumulation of the toxic aldehyde intermediate in nitrogen metabolism, such as putrescine, arginine and γ-aminobutyrate (GABA) degradations15–17. Some bacteria, for example E. coli, possess also a NADP+-dependent SSADH, GabD15,18. SSADH is ubiquitous in both prokaryotes and eukaryotes. In human, it involves in catabolism of GABA, a major neurotransmitter, its malfunction leads to a disorder SSADH deficiency19. In plants, SSADH involves in leaf development and morphogenesis20 as well as defense of abiotic stress21. And in cyanobacteria, SSADH is an essential enzyme of its uncanonical tricarboxylic acid cycle. SSADH was also found to be able to oxidize glutarate semialdehyde, participating in lysine catabolism in bacteria.

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The virulence regulator VirB from Shigella flexneri uses a CTPdependent switch mechanism to activate gene expression

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