The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4

ABSTRACT The genome of Mycobacterium tuberculosis, the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the func...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Sonam Grover, Tarina Sharma, Yadvir Singh, Sakshi Kohli, Manjunath P., Aditi Singh, Torsten Semmler, Lothar H. Wieler, Karsten Tedin, Nasreen Z. Ehtesham, Seyed E. Hasnain
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	calcium homeostasis ER localization signal granulomas unfolded protein response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7aef230cd0a349b8a9528043b29773d0
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7aef230cd0a349b8a9528043b29773d0
record_format	dspace
spelling	oai:doaj.org-article:7aef230cd0a349b8a9528043b29773d02021-11-15T16:00:26ZThe PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 410.1128/mBio.01017-182150-7511https://doaj.org/article/7aef230cd0a349b8a9528043b29773d02018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01017-18https://doaj.org/toc/2150-7511ABSTRACT The genome of Mycobacterium tuberculosis, the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism. IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.Sonam GroverTarina SharmaYadvir SinghSakshi KohliManjunath P.Aditi SinghTorsten SemmlerLothar H. WielerKarsten TedinNasreen Z. EhteshamSeyed E. HasnainAmerican Society for Microbiologyarticlecalcium homeostasisER localization signalgranulomasunfolded protein responseMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	calcium homeostasis ER localization signal granulomas unfolded protein response Microbiology QR1-502
spellingShingle	calcium homeostasis ER localization signal granulomas unfolded protein response Microbiology QR1-502 Sonam Grover Tarina Sharma Yadvir Singh Sakshi Kohli Manjunath P. Aditi Singh Torsten Semmler Lothar H. Wieler Karsten Tedin Nasreen Z. Ehtesham Seyed E. Hasnain The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4
description	ABSTRACT The genome of Mycobacterium tuberculosis, the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism. IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.
format	article
author	Sonam Grover Tarina Sharma Yadvir Singh Sakshi Kohli Manjunath P. Aditi Singh Torsten Semmler Lothar H. Wieler Karsten Tedin Nasreen Z. Ehtesham Seyed E. Hasnain
author_facet	Sonam Grover Tarina Sharma Yadvir Singh Sakshi Kohli Manjunath P. Aditi Singh Torsten Semmler Lothar H. Wieler Karsten Tedin Nasreen Z. Ehtesham Seyed E. Hasnain
author_sort	Sonam Grover
title	The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4
title_short	The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4
title_full	The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4
title_fullStr	The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4
title_full_unstemmed	The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4
title_sort	pgrs domain of <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> pe_pgrs protein rv0297 is involved in endoplasmic reticulum stress-mediated apoptosis through toll-like receptor 4
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/7aef230cd0a349b8a9528043b29773d0
work_keys_str_mv	AT sonamgrover thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT tarinasharma thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT yadvirsingh thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT sakshikohli thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT manjunathp thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT aditisingh thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT torstensemmler thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT lotharhwieler thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT karstentedin thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT nasreenzehtesham thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT seyedehasnain thepgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT sonamgrover pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT tarinasharma pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT yadvirsingh pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT sakshikohli pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT manjunathp pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT aditisingh pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT torstensemmler pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT lotharhwieler pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT karstentedin pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT nasreenzehtesham pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4 AT seyedehasnain pgrsdomainofnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentpepgrsproteinrv0297isinvolvedinendoplasmicreticulumstressmediatedapoptosisthroughtolllikereceptor4
_version_	1718426975688720384

The PGRS Domain of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4

Ejemplares similares