Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence

ABSTRACT The unfolded protein response (UPR) is a stress response pathway that is activated upon increased unfolded and/or misfolded proteins in the endoplasmic reticulum (ER), and enhanced ER stress response prolongs life span and improves immunity. However, the mechanism by which ER stress affects...

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Autores principales:	Jogender Singh, Alejandro Aballay
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Caenorhabditis elegans ER stress Pseudomonas aeruginosa immune senescence innate immunity lipoproteins Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a4b8b556e1c7474abb223f802397b863
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spelling	oai:doaj.org-article:a4b8b556e1c7474abb223f802397b8632021-11-15T15:51:30ZEndoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence10.1128/mBio.00778-172150-7511https://doaj.org/article/a4b8b556e1c7474abb223f802397b8632017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00778-17https://doaj.org/toc/2150-7511ABSTRACT The unfolded protein response (UPR) is a stress response pathway that is activated upon increased unfolded and/or misfolded proteins in the endoplasmic reticulum (ER), and enhanced ER stress response prolongs life span and improves immunity. However, the mechanism by which ER stress affects immunity remains poorly understood. Using the nematode Caenorhabditis elegans, we show that mutations in the lipoproteins vitellogenins, which are homologs of human apolipoprotein B-100, resulted in upregulation of the UPR. Lipoprotein accumulation in the intestine adversely affects the immune response and the life span of the organism, suggesting that it could be a contributing factor to immunosenescence. We show that lipoprotein accumulation inhibited the expression of several immune genes encoding proteins secreted by the intestinal cells in an IRE-1-independent manner. Our studies provide a mechanistic explanation for adverse effects caused by protein aggregation and ER stress on immunity and highlight the role of an IRE-1-independent pathway in the suppression of the expression of genes encoding secreted proteins. IMPORTANCE Increased accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) leads to enhanced ER stress. However, the mechanism(s) by which ER stress affects immunity remain understudied. Using the nematode C. elegans, we showed that mutations in lipoproteins lead to their accumulation in the intestine, causing ER stress and adversely affecting the life span of the organisms and their resistance to pathogen infection. Our results indicate that the ER stress caused by lipoprotein accumulation significantly reduced the levels of expression of genes encoding secreted immune effectors, contributing to immunosenescence. It is known that ER stress may suppress gene expression via IRE-1, which is a sensor of ER stress. The novel mechanism uncovered in our study is IRE-1 independent, which highlights the role of a novel process by which ER stress suppresses innate immunity.Jogender SinghAlejandro AballayAmerican Society for MicrobiologyarticleCaenorhabditis elegansER stressPseudomonas aeruginosaimmune senescenceinnate immunitylipoproteinsMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Caenorhabditis elegans ER stress Pseudomonas aeruginosa immune senescence innate immunity lipoproteins Microbiology QR1-502
spellingShingle	Caenorhabditis elegans ER stress Pseudomonas aeruginosa immune senescence innate immunity lipoproteins Microbiology QR1-502 Jogender Singh Alejandro Aballay Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
description	ABSTRACT The unfolded protein response (UPR) is a stress response pathway that is activated upon increased unfolded and/or misfolded proteins in the endoplasmic reticulum (ER), and enhanced ER stress response prolongs life span and improves immunity. However, the mechanism by which ER stress affects immunity remains poorly understood. Using the nematode Caenorhabditis elegans, we show that mutations in the lipoproteins vitellogenins, which are homologs of human apolipoprotein B-100, resulted in upregulation of the UPR. Lipoprotein accumulation in the intestine adversely affects the immune response and the life span of the organism, suggesting that it could be a contributing factor to immunosenescence. We show that lipoprotein accumulation inhibited the expression of several immune genes encoding proteins secreted by the intestinal cells in an IRE-1-independent manner. Our studies provide a mechanistic explanation for adverse effects caused by protein aggregation and ER stress on immunity and highlight the role of an IRE-1-independent pathway in the suppression of the expression of genes encoding secreted proteins. IMPORTANCE Increased accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) leads to enhanced ER stress. However, the mechanism(s) by which ER stress affects immunity remain understudied. Using the nematode C. elegans, we showed that mutations in lipoproteins lead to their accumulation in the intestine, causing ER stress and adversely affecting the life span of the organisms and their resistance to pathogen infection. Our results indicate that the ER stress caused by lipoprotein accumulation significantly reduced the levels of expression of genes encoding secreted immune effectors, contributing to immunosenescence. It is known that ER stress may suppress gene expression via IRE-1, which is a sensor of ER stress. The novel mechanism uncovered in our study is IRE-1 independent, which highlights the role of a novel process by which ER stress suppresses innate immunity.
format	article
author	Jogender Singh Alejandro Aballay
author_facet	Jogender Singh Alejandro Aballay
author_sort	Jogender Singh
title	Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
title_short	Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
title_full	Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
title_fullStr	Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
title_full_unstemmed	Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
title_sort	endoplasmic reticulum stress caused by lipoprotein accumulation suppresses immunity against bacterial pathogens and contributes to immunosenescence
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/a4b8b556e1c7474abb223f802397b863
work_keys_str_mv	AT jogendersingh endoplasmicreticulumstresscausedbylipoproteinaccumulationsuppressesimmunityagainstbacterialpathogensandcontributestoimmunosenescence AT alejandroaballay endoplasmicreticulumstresscausedbylipoproteinaccumulationsuppressesimmunityagainstbacterialpathogensandcontributestoimmunosenescence
_version_	1718427357731094528

Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence

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