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Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mycobacterium tuberculosis Mycobacterium tuberculosis CDC1551 Homo sapiens Mycobacterium tuberculosis H37Rv Macaca mulatta

PROVIDER: GSE118869 | GEO | 2018/08/22

REPOSITORIES: GEO

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Mycobacterium tuberculosis sensor kinase DosS modulates the autophagosome in a DosR-independent manner.

Project description:Dormancy is a key characteristic of the intracellular life-cycle of Mtb. The importance of sensor kinase DosS in mycobacteria are attributed in part to our current findings that DosS is required for both persistence and full virulence of Mtb. Here we show that DosS is also required for optimal replication in macrophages and involved in the suppression of TNF-? and autophagy pathways. Silencing of these pathways during the infection process restored full virulence in Mtb?dosS mutant. Notably, a mutant of the response regulator DosR did not exhibit the attenuation in macrophages, suggesting that DosS can function independently of DosR. We identified four DosS targets in Mtb genome; Rv0440, Rv2859c, Rv0994, and Rv0260c. These genes encode functions related to hypoxia adaptation, which are not directly controlled by DosR, e.g., protein recycling and chaperoning, biosynthesis of molybdenum cofactor and nitrogen metabolism. Our results strongly suggest a DosR-independent role for DosS in Mtb.

| S-EPMC6754383 | biostudies-literature

Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner [II]

Project description:Transcriptional profiling of bacterial RNA samples from infected Rhesus Bone Marrow Derived Macrophages (RhBMDMs) compared to RNA isolated from respective in vitro grwon cultures viz M. tuberculosis H37Rv or Isogeneic mutant MtbdosS

2018-08-22 | GSE118867 | GEO

Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner [I]

Project description:Transcriptional profiling of RNA samples from un-infected Rhesus Bone Marrow Derived Macrophages (RhBMDMs) exposed to IMDM complete media used as control were compared to RNA from RhBMDMs infected for 24 hr with 'dos' mutants of Mtb viz. MtbΔdosR, MtbΔdosS, or MtbΔdosT

2018-08-22 | GSE118866 | GEO

Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner

Project description:Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner

| PRJNA487069 | ENA

Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner [I]

Project description:Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner [I]

| PRJNA487072 | ENA

Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner [II]

Project description:Mycobacterium tuberculosis Sensor Kinase DosS Modulates the Autophagosome in a DosR-independent Manner [II]

| PRJNA487075 | ENA

The DosS-DosT/DosR Mycobacterial Sensor System.

Project description:DosS/DosR is a two-component regulatory system in which DosS, a heme-containing sensor also known as DevS, under certain conditions undergoes autophosphorylation and then transfers the phosphate to DosR, a DNA-binding protein that controls the entry of Mycobacterium tuberculosis and other mycobacteria into a latent, dormant state. DosT, a second sensor closely related to DosS, is present in M. tuberculosis and participates in the control of the dormancy response mediated by DosR. The binding of phosphorylated DosR to DNA initiates the expression of approximately fifty dormancy-linked genes. DosT is accepted to be a gas sensor that is activated in the ferrous state by the absence of an oxygen ligand or by the binding of NO or CO. DosS functions in a similar fashion as a gas sensor, but contradictory evidence has led to the suggestion that it also functions as a redox state sensor. This review focuses on the structure, biophysical properties, and function of the DosS/DosT heme sensors.

| S-EPMC4082495 | biostudies-literature

Unique roles of DosT and DosS in DosR regulon induction and Mycobacterium tuberculosis dormancy.

Project description:In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, which is important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors have been postulated biochemically, but their roles in vivo have remained unclear. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild-type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild-type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state.

| S-EPMC2715697 | biostudies-literature

Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor.

Project description:A fundamental challenge to the study of oxidative stress responses of Mycobacterium tuberculosis (Mtb) is to understand how the protective host molecules are sensed and relayed to control bacilli gene expression. The genetic response of Mtb to hypoxia and NO is controlled by the sensor kinases DosS and DosT and the response regulator DosR through activation of the dormancy/NO (Dos) regulon. However, the regulatory ligands of DosS and DosT and the mechanism of signal sensing were unknown. Here, we show that both DosS and DosT bind heme as a prosthetic group and that DosS is rapidly autooxidized to attain the met (Fe3+) form, whereas DosT exists in the O2-bound (oxy) form. EPR and UV-visible spectroscopy analysis showed that O2, NO, and CO are ligands of DosS and DosT. Importantly, we demonstrate that the oxidation or ligation state of the heme iron modulates DosS and DosT autokinase activity and that ferrous DosS, and deoxy DosT, show significantly increased autokinase activity compared with met DosS and oxy DosT. Our data provide direct proof that DosS functions as a redox sensor, whereas DosT functions as a hypoxia sensor, and that O2, NO, and CO are modulatory ligands of DosS and DosT. Finally, we identified a third potential dormancy signal, CO, that induces the Mtb Dos regulon. We conclude that Mtb has evolved finely tuned redox and hypoxia-mediated sensing strategies for detecting O2, NO, and CO. Data presented here establish a paradigm for understanding the mechanism of bacilli persistence.

| S-EPMC1906723 | biostudies-literature

<i>Mycobacterium tuberculosis</i> Calcium Pump CtpF Modulates the Autophagosome in an mTOR-Dependent Manner.

Project description:Calcium is a very important second messenger, whose concentration in various cellular compartments is under tight regulation. A disturbance in the levels of calcium in these compartments can play havoc in the cell, as it regulates various cellular processes by direct or indirect mechanisms. Here, we have investigated the functional importance of a calcium transporting P2A ATPase, CtpF of Mycobacterium tuberculosis (Mtb) in the pathogen's interaction with the host. Among its uncanny ways of dealing with the host with umpteen strategies for survival and persistence in humans, CtpF is identified as a new player. The levels of ctpF are upregulated in macrophage stresses like hypoxia, high nitric oxide levels and acidic pH. Using confocal microscopy and fluorimetry, we show that CtpF effluxes calcium in macrophages in early stages of Mtb infection. Downregulation of ctpF expression by conditional knockdown resulted in perturbation of host calcium levels and consequent decreased activation of mTOR. We present a mechanism how calcium efflux by the pathogen inhibits mTOR-dependent autophagy and enhances bacterial survival. Our work highlights how Mtb engages its metal efflux pumps to exploit host autophagic process for its proliferation.

| S-EPMC7525011 | biostudies-literature

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