A periplasmic cinched protein is required for siderophore secretion and virulence of Mycobacterium tuberculosis

Abstract

Iron is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis. To acquire iron from the host, M. tuberculosis uses the siderophores called mycobactins and carboxymycobactins. Here, we show that the rv0455c gene is essential for M. tuberculosis to grow in low-iron medium and that secretion of both mycobactins and carboxymycobactins is drastically reduced in the rv0455c deletion mutant. Both water-soluble and membrane-anchored Rv0455c are functional in siderophore secretion, supporting an intracellular role. Lack of Rv0455c results in siderophore toxicity, a phenotype observed for other siderophore secretion mutants, and severely impairs replication of M. tuberculosis in mice, demonstrating the importance of Rv0455c and siderophore secretion during disease. The crystal structure of a Rv0455c homolog reveals a novel protein fold consisting of a helical bundle with a ‘cinch’ formed by an essential intramolecular disulfide bond. These findings advance our understanding of the distinct M. tuberculosis siderophore secretion system.

Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

“…Therefore, there is a growing interest in targeting the pathways involved in its acquisition [ 34 , 35 , 36 ]. In detail, the production of siderophores (mycobactins and carboxymycobactins) has been shown to be of crucial importance; hence, proteins involved in their assembly, transport, and functionality have been proposed as potential targets [ 37 , 38 , 39 , 40 , 41 , 42 ]. Moreover, siderophores have been shown to prevent phagosome maturation inside macrophages and induce hypoxia-like toxicity in host cells [ 7 , 43 ].…”

TargetingMycobacterium tuberculosisiron-scavenging tools: a recent update on siderophores inhibitors

“…170 Moreover, M.tb with the deleted rv0455c gene failed to replicate inside the mice. 169 The biosynthesis of mycobactin is shown in Scheme 1. 171…”

“…In addition, the lack rv0455c gene is responsible for siderophore toxicity. 169 The accumulation of intracellular siderophores is toxic to the M.tb . 170 Moreover, M.tb with the deleted rv0455c gene failed to replicate inside the mice.…”

Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages

“…The M.tb Rv1096 strain was recently found to accelerate its growth in RAW 264.7 cells and dampen pro-inflammatory cytokine production as well as NF-κB and MAPK signaling [ 128 ]. The M.tb protein Rv0455c was shown to be a virulence factor as a Δrv0455c mutant had impaired growth in lung and spleen homogenates due to decreased iron uptake [ 129 ]. Different strains may induce different immune cell and cytokine responses, such as IL-22 being important for protective immunity against the hypervirulent HN878 strain but not against the lesser virulent H 37 R v strain [ 130 ].…”