@article{bf813f27c18b4c39b94c42af68507dea,
title = "The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response",
abstract = "Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.",
keywords = "ATF5, CP: Metabolism, CP: Molecular biology, UPR, cholecystokinin, colitis, epithelial barrier, host-pathogen interaction, hyperglycemia, leptin, mitochondria, satiety",
author = "Douja Chamseddine and Mahmud, {Siraje A.} and Westfall, {Aundrea K.} and Castoe, {Todd A.} and Berg, {Rance E.} and Pellegrino, {Mark W.}",
note = "Funding Information: The authors thank Dr. Christopher Gibson at iHisto Inc. and Dr. Neda Habibi Arejan (UTA) for histological assessment. We are grateful for services provided by the UTA Animal Core Facility and to Dr. Walter Schargel for advice on statistical analysis. Research funds were provided by the National Institutes of Health (R35GM128885) and the Cancer Prevention & Research Institute of Texas (RR160053) to M.W.P. a CPRIT Scholar in Cancer Research. D.C. and M.W.P. designed the study. Supervision of the study was performed by R.E.B. and M.W.P. Most experimental work was conducted by D.C. RNA-seq data were analyzed by S.A.M, A.K.W. and T.A.C. Select assay development was assisted by S.A.M. Figures and supplementary figures/tables were generated by D.C. with the exception of those pertaining to transcriptomic analysis, which were developed by A.K.W. Manuscript writing was performed by D.C. and M.W.P. Comments on the manuscript were provided by A.K.W. T.A.C. and R.E.B. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = dec,
day = "13",
doi = "10.1016/j.celrep.2022.111789",
language = "English",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}