Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of
            <i>Mycobacterium tuberculosis</i>
            PPE37 Protein

Ahmad, Javeed; Farhana, Aisha; Pancsa, Rita; Arora, Simran; Srinivasan, Alagiri; Tyagi, Anil K.; Babu, Madan Mohan; Ehtesham, Nasreen Z.; Hasnain, Seyed E.

doi:10.1128/mbio.01712-17

Cited by 42 publications

(46 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was recently reported that PPE37 is exported, with the protein found primarily in the cell membrane fraction, and that it possesses a eukaryotic-type signal sequence from residues 1 to 40, although the details for how the signal sequence was determined were not reported (31). We analyzed the M. tuberculosis PPE37 sequence using SignalP, TatP, LipoP, and TargetP to predict potential secretion signals.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, PPE37 does not have a conventional signal peptide that can be detected by the SignalP, TatP, or LipoP algorithm, but the higher score than nonsecretory proteins and the cleavage site predictions suggest that it may possess a nonclassical signal peptide. As PPE37 has two transmembrane domains and as the protein was detected in the cell membrane fraction (31), it is likely to be an integral membrane protein. Interestingly, the cleavage site predictions occur either in the amino acids deleted from the BCG PPE37 protein or immediately adjacent to the deletion, suggesting that the BCG PPE37 protein might be processed differently.…”

Section: Resultsmentioning

confidence: 99%

“…Genetic variation of ppe37 in M. tuberculosis. Recently, Ahmad et al reported significant variability in PPE37 from an analysis of 28 M. tuberculosis strains with completed genomes and presented a protein alignment of PPE37 proteins from three representative strains (H37Rv, F11, and 49-02) that demonstrated that the F11 sequence is identical to that of H37Rv PPE37 on the N terminus but has an altered C terminus and that the 49-02 sequence is identical to that of H37Rv PPE37 on the C terminus but has an altered N terminus (31). However, further explanation of the variability was not discussed.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, M. tuberculosis clearly has additional means of releasing iron from heme that do not require MhuD. However, the localization of PPE37 in the cell membrane fraction (31) and the likely presence of a signal peptide in PPE37 argue against a role for PPE37 in cytosolic degradation of heme although this possibility cannot be ruled out at present. Finally, deletion of ppe37 (or expression of a nonfunctional PPE37 by BCG) might have a general effect on cell wall permeability which impacts HIA in a nonspecific manner; i.e., it might make the cell wall less permeable to diffusion of heme.…”

Section: Figmentioning

confidence: 95%

“…In one study, expression of M. tuberculosis PPE37 by M. smegmatis resulted in a lower level of proinflammatory cytokines secreted by infected macrophages, but the mechanism by which expression of recombinant PPE37 interfered with the proinflammatory cytokine response was not determined (44). Recently, a second study examining the function of PPE37 demonstrated that PPE37 appears to be exported as it is predominantly located in the cell membrane fraction of M. tuberculosis grown under low-iron conditions (31). The authors also ascribed different host-modulating functions to the N-terminal and C-terminal segments of PPE37 when the segments are transfected into the human monocytic THP-1 cell line.…”

Section: Figmentioning

confidence: 99%

See 4 more Smart Citations

PPE37 Is Essential for Mycobacterium tuberculosis Heme-Iron Acquisition (HIA), and a Defective PPE37 in Mycobacterium bovis BCG Prevents HIA

2019

View full text Add to dashboard Cite

Mycobacterium tuberculosis, one of the world’s leading causes of death, must acquire nutrients, such as iron, from the host to multiply and cause disease. Iron is an essential metal and M. tuberculosis possesses two different systems to acquire iron from its environment: siderophore-mediated iron acquisition (SMIA) and heme-iron acquisition (HIA), involving uptake and degradation of heme to release ferrous iron. We have discovered that Mycobacterium bovis BCG, the tuberculosis vaccine strain, is severely deficient in HIA, and we exploited this phenotypic difference between BCG and M. tuberculosis to identify genes involved in HIA by complementing BCG’s defect with a fosmid library. We identified ppe37, an iron-regulated PPE family gene, as being essential for HIA. BCG complemented with M. tuberculosis ppe37 exhibits HIA as efficient as that of M. tuberculosis, achieving robust growth with <0.2 µM hemin. Conversely, deletion of ppe37 from M. tuberculosis results in a strain severely attenuated in HIA, with a phenotype nearly identical to that of BCG, requiring a 200-fold higher concentration of hemin to achieve growth equivalent to that of its parental strain. A nine-amino-acid deletion near the N terminus of BCG PPE37 (amino acids 31 to 39 of the M. tuberculosis PPE37 protein) underlies BCG’s profound defect in HIA. Significant genetic variability exists in ppe37 genes across different M. tuberculosis strains, with more than 60% of sequences from completely sequenced M. tuberculosis genomes having mutations that result in altered PPE37 proteins; furthermore, these altered PPE37 proteins are nonfunctional in HIA. Our findings should allow delineation of the relative roles of HIA and SMIA in M. tuberculosis pathogenesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Figmentioning

confidence: 95%

Section: Figmentioning

confidence: 99%

See 3 more Smart Citations

PPE37 Is Essential for Mycobacterium tuberculosis Heme-Iron Acquisition (HIA), and a Defective PPE37 in Mycobacterium bovis BCG Prevents HIA

2019

View full text Add to dashboard Cite

show abstract

Disorder‐to‐order transition in PE–PPE proteins of Mycobacterium tuberculosis augments the pro‐pathogen immune response

et al. 2019

Self Cite

View full text Add to dashboard Cite

A growing body of evidence supports the hypothesis that intrinsically disordered proteins often mediate host–pathogen interactions and modulate host functions for pathogen survival and virulence. Mycobacterium tuberculosis (M.tb) has evolved largely through reductive evolution, with a few exceptions such as the glycine–alanine‐rich PE–PPE/PGRS protein family, which has been expanding in pathogenic mycobacteria. Here, our analyses of the M.tb proteome and secretome revealed that the PE–PGRS subfamily is enriched for disordered regions and disordered binding sites, pointing to their importance in host–pathogen interactions. As a case study, the secondary structure of PE35–PPE68 and PE32–PPE65 of the pathogenesis‐related RD1 and RD8 regions was analyzed through Fourier‐transform infrared spectroscopy. These disordered proteins displayed a considerable structural shift from disordered to ordered while engaged in the formation of complexes. While these proteins are immunogenic individually and enhance the pro‐pathogen response, their corresponding complexes enhanced the responses manifold as displayed here by PE35 and PPE68. It is likely that M.tb exploits such disorder–order structural dynamics as a strategy to mount a pro‐pathogen response and subvert host defense for productive infection. This functional gain also serves as a means to compensate genomic content loss due to reductive evolution.

show abstract

Regulation of Type I Interferon and Autophagy in Immunity against Mycobacterium Tuberculosis: Role of CGAS and STING1

Malik,

Shariq,

Sheikh

et al. 2024

Advanced Biology

View full text Add to dashboard Cite

Mycobacterium tuberculosis (M. tb) is a significant intracellular pathogen responsible for numerous infectious disease‐related deaths worldwide. It uses ESX‐1 T7SS to damage phagosomes and to enter the cytosol of host cells after phagocytosis. During infection, M. tb and host mitochondria release dsDNA, which activates the CGAS‐STING1 pathway. This pathway leads to the production of type I interferons and proinflammatory cytokines and activates autophagy, which targets and degrades bacteria within autophagosomes. However, the role of type I IFNs in immunity against M. tb is controversial. While previous research has suggested a protective role, recent findings from cgas‐sting1 knockout mouse studies have contradicted this. Additionally, a study using knockout mice and non‐human primate models uncovered a new mechanism by which neutrophils recruited to lung infections form neutrophil extracellular traps. Activating plasmacytoid dendritic cells causes them to produce type I IFNs, which interfere with the function of interstitial macrophages and increase the likelihood of tuberculosis. Notably, M. tb uses its virulence proteins to disrupt the CGAS‐STING1 signaling pathway leading to enhanced pathogenesis. Investigating the CGAS‐STING1 pathway can help develop new ways to fight tuberculosis.

show abstract

Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of Mycobacterium tuberculosis PPE37 Protein

Cited by 42 publications

References 41 publications

PPE37 Is Essential for Mycobacterium tuberculosis Heme-Iron Acquisition (HIA), and a Defective PPE37 in Mycobacterium bovis BCG Prevents HIA

PPE37 Is Essential for Mycobacterium tuberculosis Heme-Iron Acquisition (HIA), and a Defective PPE37 in Mycobacterium bovis BCG Prevents HIA

Disorder‐to‐order transition in PE–PPE proteins of Mycobacterium tuberculosis augments the pro‐pathogen immune response

Regulation of Type I Interferon and Autophagy in Immunity against Mycobacterium Tuberculosis: Role of CGAS and STING1

Contact Info

Product

Resources

About