TY - JOUR
T1 - Endoplasmic reticulum stress caused by lipoprotein accumulation suppresses immunity against bacterial pathogens and contributes to immunosenescence
AU - Singh, Jogender
AU - Aballay, Alejandro
N1 - Funding Information:
Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by grants from the National Institutes of Health (GM0709077 and AI117911). We thank Barth Grant (Rutgers University, Piscataway, NJ) for providing the vit-2::gfp plasmid. We declare that we have no competing financial interests.
Publisher Copyright:
© 2017 Singh and Aballay.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - Caenorhabditis elegans
KW - ER stress
KW - Immune senescence
KW - Innate immunity
KW - Lipoproteins
KW - Pseudomonas aeruginosa
KW - Unfolded protein response
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U2 - 10.1128/mBio.00778-17
DO - 10.1128/mBio.00778-17
M3 - Article
C2 - 28559483
AN - SCOPUS:85022022373
SN - 2161-2129
VL - 8
JO - mBio
JF - mBio
IS - 3
M1 - e00778-17
ER -