The proteins belonging to the Fur family are global regulators of gene expression involved in the response to several environmental stresses and to the maintenance of divalent cation homeostasis. The Mycobacterium tuberculosis genome encodes two Fur-like proteins, FurA and a protein formerly annotated FurB. Since in this paper we show that it represents a zinc uptake regulator, we refer to it as Zur. The gene encoding Zur is found in an operon together with the gene encoding a second transcriptional regulator (Rv2358). In a previous work we demonstrated that Rv2358 is responsible for the zinc-dependent repression of the Rv2358-zur operon, favoring the hypothesis that these genes represent key regulators of zinc homeostasis. In this study we generated a zur mutant in M. tuberculosis, examined its phenotype, and characterized the Zur regulon by DNA microarray analysis. Thirty-two genes, presumably organized in 16 operons, were found to be upregulated in the zur mutant. Twenty-four of them belonged to eight putative transcriptional units preceded by a conserved 26-bp palindrome. Electrophoretic mobility shift experiments demonstrated that Zur binds to this palindrome in a zinc-dependent manner, suggesting its direct regulation of these genes. The proteins encoded by Zurregulated genes include a group of ribosomal proteins, three putative metal transporters, the proteins belonging to early secretory antigen target 6 (ESAT-6) cluster 3, and three additional proteins belonging to the ESAT-6/culture filtrate protein 10 (CFP-10) family known to contain immunodominant epitopes in the T-cell response to M. tuberculosis infection.Mycobacterium tuberculosis is a human pathogen that infects and replicates within macrophages. This microorganism lives in phagosomes that fail to fuse with lysosomes and has adapted its lifestyle to survive and replicate in the changing environment within the endosomal system (20).The long-recognized phenomenon of nutritional immunity, in which sequestration of iron and possibly other metals occurs as a nonspecific host response to infection (2), hints in general terms at the possibility of a keen competition between host and parasite for essential metal ions. A critical point is the bacterial ability to compete with the host for nutrients, and the acquisition of metal ions has important implications for intracellular survival.Pathogenic bacteria respond to such limitations by inducing metabolic functions that overcome nutritional deficiencies and/or inducing virulence functions required for immediate survival and spread to subsequent anatomical sites of infection. The outcome of this competition between the host cell and the microorganism is certainly one of the most important factors determining the ability of pathogens to multiply and cause disease (41).Metalloregulatory proteins sense the intracellular levels of specific metal ions and mediate a transcriptional response aimed at restoring homeostasis when these levels are altered. In prokaryotes, these transcriptional regulators are clustered...

Mycobacterium tuberculosis is a remarkable pathogen capable of adapting and surviving in various harsh conditions. Correct gene expression regulation is essential for the success of this process. The reversible association of different s factors is a common mechanism for reprogramming bacterial RNA polymerase and modulating the transcription of numerous genes. Thirteen putative s factors are encoded in the M. tuberculosis genome, several being important for virulence. Here, we analyse the latest information available on mycobacterial s factors and discuss their roles in the physiology and virulence of M. tuberculosis.

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