Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein

ABSTRACT Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not...

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Autores principales:	Javeed Ahmad, Aisha Farhana, Rita Pancsa, Simran Kaur Arora, Alagiri Srinivasan, Anil Kumar Tyagi, Madan Mohan Babu, Nasreen Zafar Ehtesham, Seyed Ehtesham Hasnain
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	apoptosis eukaryotic linear motifs intrinsically disordered regions molecular mimicry nuclear localization signal tolerogenic immune cells Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b0755ae2309d45efba5fd88f40d1044f
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spelling	oai:doaj.org-article:b0755ae2309d45efba5fd88f40d1044f2021-11-15T15:53:26ZContrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein10.1128/mBio.01712-172150-7511https://doaj.org/article/b0755ae2309d45efba5fd88f40d1044f2018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01712-17https://doaj.org/toc/2150-7511ABSTRACT Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not known. The Mycobacterium-specific PE-PPE protein family has several members with unusually high levels of structural disorder and disorder-promoting Ala/Gly residues. PPE37 protein, a member of this family, carries an N-terminal PPE domain capable of iron binding, two transmembrane domains, and a disordered C-terminal segment harboring ELMs and a eukaryotic nuclear localization signal (NLS). PPE37, expressed as a function of low iron stress, was cleaved by M. tuberculosis protease into N- and C-terminal segments. A recombinant N-terminal segment (P37N) caused proliferation and differentiation of monocytic THP-1 cells, into CD11c, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin)-positive semimature dendritic cells exhibiting high interleukin-10 (IL-10) but negligible IL-12 and also low tumor necrosis factor alpha (TNF-α) secretion—an environment suitable for maintaining tolerogenic immune cells. The C-terminal segment entered the macrophage nucleus and induced caspase-3-dependent apoptosis of host cells. Mice immunized with recombinant PPE37FL and PPE37N evoked strong anti-inflammatory response, validating the in vitro immunostimulatory effect. Analysis of the IgG response of PPE37FL and PPE37N revealed significant immunoreactivities in different categories of TB patients, viz. pulmonary TB (PTB) and extrapulmonary TB (EPTB), vis-a-vis healthy controls. These results support the role of IDPs in performing contrasting activities to modulate the host processes, possibly through molecular mimicry and cross talk in two spatially distinct host environments which may likely aid M. tuberculosis survival and pathogenesis. IMPORTANCE To hijack the human host cell machinery to enable survival inside macrophages, the pathogen Mycobacterium tuberculosis requires a repertoire of proteins that can mimic host protein function and modulate host cell machinery. Here, we have shown how a single protein can play multiple functions and hijack the host cell for the benefit of the pathogen. Full-length membrane-anchored PPE37 protein is cleaved into N- and C-terminal domains under iron-depleted conditions. The N-terminal domain facilitates the propathogen semimature tolerogenic state of dendritic cells, whereas the C-terminal segment is localized into host cell nucleus and induces apoptosis. The immune implications of these in vitro observations were assessed and validated in mice and also human TB patients. This study presents novel mechanistic insight adopted by M. tuberculosis to survive inside host cells.Javeed AhmadAisha FarhanaRita PancsaSimran Kaur AroraAlagiri SrinivasanAnil Kumar TyagiMadan Mohan BabuNasreen Zafar EhteshamSeyed Ehtesham HasnainAmerican Society for Microbiologyarticleapoptosiseukaryotic linear motifsintrinsically disordered regionsmolecular mimicrynuclear localization signaltolerogenic immune cellsMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	apoptosis eukaryotic linear motifs intrinsically disordered regions molecular mimicry nuclear localization signal tolerogenic immune cells Microbiology QR1-502
spellingShingle	apoptosis eukaryotic linear motifs intrinsically disordered regions molecular mimicry nuclear localization signal tolerogenic immune cells Microbiology QR1-502 Javeed Ahmad Aisha Farhana Rita Pancsa Simran Kaur Arora Alagiri Srinivasan Anil Kumar Tyagi Madan Mohan Babu Nasreen Zafar Ehtesham Seyed Ehtesham Hasnain Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein
description	ABSTRACT Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not known. The Mycobacterium-specific PE-PPE protein family has several members with unusually high levels of structural disorder and disorder-promoting Ala/Gly residues. PPE37 protein, a member of this family, carries an N-terminal PPE domain capable of iron binding, two transmembrane domains, and a disordered C-terminal segment harboring ELMs and a eukaryotic nuclear localization signal (NLS). PPE37, expressed as a function of low iron stress, was cleaved by M. tuberculosis protease into N- and C-terminal segments. A recombinant N-terminal segment (P37N) caused proliferation and differentiation of monocytic THP-1 cells, into CD11c, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin)-positive semimature dendritic cells exhibiting high interleukin-10 (IL-10) but negligible IL-12 and also low tumor necrosis factor alpha (TNF-α) secretion—an environment suitable for maintaining tolerogenic immune cells. The C-terminal segment entered the macrophage nucleus and induced caspase-3-dependent apoptosis of host cells. Mice immunized with recombinant PPE37FL and PPE37N evoked strong anti-inflammatory response, validating the in vitro immunostimulatory effect. Analysis of the IgG response of PPE37FL and PPE37N revealed significant immunoreactivities in different categories of TB patients, viz. pulmonary TB (PTB) and extrapulmonary TB (EPTB), vis-a-vis healthy controls. These results support the role of IDPs in performing contrasting activities to modulate the host processes, possibly through molecular mimicry and cross talk in two spatially distinct host environments which may likely aid M. tuberculosis survival and pathogenesis. IMPORTANCE To hijack the human host cell machinery to enable survival inside macrophages, the pathogen Mycobacterium tuberculosis requires a repertoire of proteins that can mimic host protein function and modulate host cell machinery. Here, we have shown how a single protein can play multiple functions and hijack the host cell for the benefit of the pathogen. Full-length membrane-anchored PPE37 protein is cleaved into N- and C-terminal domains under iron-depleted conditions. The N-terminal domain facilitates the propathogen semimature tolerogenic state of dendritic cells, whereas the C-terminal segment is localized into host cell nucleus and induces apoptosis. The immune implications of these in vitro observations were assessed and validated in mice and also human TB patients. This study presents novel mechanistic insight adopted by M. tuberculosis to survive inside host cells.
format	article
author	Javeed Ahmad Aisha Farhana Rita Pancsa Simran Kaur Arora Alagiri Srinivasan Anil Kumar Tyagi Madan Mohan Babu Nasreen Zafar Ehtesham Seyed Ehtesham Hasnain
author_facet	Javeed Ahmad Aisha Farhana Rita Pancsa Simran Kaur Arora Alagiri Srinivasan Anil Kumar Tyagi Madan Mohan Babu Nasreen Zafar Ehtesham Seyed Ehtesham Hasnain
author_sort	Javeed Ahmad
title	Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein
title_short	Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein
title_full	Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein
title_fullStr	Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein
title_full_unstemmed	Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein
title_sort	contrasting function of structured n-terminal and unstructured c-terminal segments of <italic toggle="yes">mycobacterium tuberculosis</italic> ppe37 protein
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/b0755ae2309d45efba5fd88f40d1044f
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Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of <italic toggle="yes">Mycobacterium tuberculosis</italic> PPE37 Protein

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