How autophagy controls the intestinal epithelial barrier

Foerster, Elisabeth G.; Mukherjee, Tapas; Cabral-Fernandes, Liliane; Rocha, Juliana Dutra B.; Girardin, Stephen E.; Philpott, Dana J.

doi:10.1080/15548627.2021.1909406

Cited by 180 publications

(130 citation statements)

References 180 publications

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“…Autophagy is crucial to protect cells against various stresses and represents a key component of the innate immunity, especially by contributing to pathogen clearance and by modulating the inflammatory response in the gut. 13 , 14 Autophagy has also been described as a protective mechanism against fungal infections. 15 However, conflicting data exist on the role of autophagy in vivo during C. albicans infections.…”

Section: Introductionmentioning

confidence: 99%

“…Autophagy has been described to contribute to multiple features of the protective role of epithelial cells, including tight junctions’ maintenance and cell death mitigation. 1 , 14 Here, we explored in depth the role of autophagy and autophagy-related proteins in human epithelial cells during C. albicans infection, focusing on intestinal epithelial cells as the main portal of entry for C. albicans -disseminated infections. We showed that key autophagy-related proteins are recruited at C. albicans entry sites.…”

Section: Introductionmentioning

confidence: 99%

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Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans

et al. 2022

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Candida albicans ( C. albicans ) is an opportunistic pathogen causing infections ranging from superficial to life-threatening disseminated infections. In a susceptible host, C. albicans is able to translocate through the gut barrier, promoting its dissemination into deeper organs. C. albicans hyphae can invade human epithelial cells by two well-documented mechanisms: epithelial-driven endocytosis and C. albicans -driven active penetration. One mechanism by which host cells protect themselves against intracellular C. albicans is termed autophagy. The protective role of autophagy during C. albicans infection has been investigated in myeloid cells; however, far less is known regarding the role of this process during the infection of epithelial cells. In the present study, we investigated the role of autophagy-related proteins during the infection of epithelial cells, including intestinal epithelial cells and gut explants, by C. albicans . Using cell imaging, we show that key molecular players of the autophagy machinery (LC3-II, PI3P, ATG16L1, and WIPI2) were recruited at Candida invasion sites. We deepened these observations by electron microscopy analyses that reveal the presence of autophagosomes in the vicinity of invading hyphae. Importantly, these events occur during active penetration of C. albicans into host cells and are associated with plasma membrane damage. In this context, we show that the autophagy-related key proteins ATG5 and ATG16L1 contribute to plasma membrane repair mediated by lysosomal exocytosis and participate in protecting epithelial cells against C. albicans -induced cell death. Our findings provide a novel mechanism by which epithelial cells, forming the first line of defense against C. albicans in the gut, can react to limit C. albicans invasion.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans

et al. 2022

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“…12 Studies have shown that in experimental colitis models, the expression of TJ protein isoforms (including claudin, occludin, and ZOs) was decreased and often accompanied by an increase in intestinal epithelial permeability. 13 , 14 Bacteria, toxins, and other substances in the intestinal cavity can disrupt and break through the intestinal epithelial cells’ TJs, penetrate the intestinal mucosa, and enter other tissue, organs, and the circulatory system, causing bacterial and toxin translocation. Concurrently, intestinal inflammation causes the release of a large number of inflammatory factors that affect epithelial barrier function and can lead to the development of IBD.…”

Section: Discussionmentioning

confidence: 99%

The Correlation Between MYO9B Gene Polymorphism and Inflammatory Bowel Disease in the Guangxi Zhuang Population

Zeng¹,

Lv²,

Liu³

et al. 2021

IJGM

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Objective:To analyze the correlation between site rs962917 of the MYO9B gene and inflammatory bowel disease (IBD) in the Guangxi Zhuang nationality population. Methods: The intestinal mucosa tissue of 153 IBD subjects (Han and Zhuang patients only) in the Guangxi Zhuang autonomous region comprised the case group, and the intestinal mucosa tissue of 155 healthy subjects (Han and Zhuang patients only) in the same region represented the control group. Deoxyribonucleic acid was extracted from the intestinal mucosa tissue of each experimental group, and the MYO9B gene-target fragment containing the single nucleotide polymorphism (SNP) site rs962917 was designed. Finally, polymerase chain reaction products were obtained by amplification, analyzed, and compared using the sequencing results. Results:The results indicated that the genotype frequency of the MYO9B SNP site rs962917 between Crohn's disease (CD) and control groups of Zhuang and Han participants differed significantly (P < 0.05). Furthermore, the genotype frequency of MYO9B site rs962917 differed significantly between the Zhuang and Han population groups (P < 0.05). Conclusion: Site rs962917 of the MYO9B gene is related to CD susceptibility and incidence among the Guangxi Zhuang population.

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“…Many reports have found evidence indicating that autophagy-related genes (Atg5, Beclin 1, Atg16L1, and UV radiation resistance-associated gene/UVRAG) are either mutated or down-regulated in CRC cells ( 9 – 12 ). Furthermore, accumulating evidence shows that autophagy functions as a transformational switch when a cell shifts from normal to malignant in CRC tumorigenesis ( 13 ). However, the mechanism remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer

et al. 2021

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Many studies reported that microRNAs (miRNAs) target autophagy-related genes to affect carcinogenesis, however, autophagy-deficiency-related miRNA dysfunction in cancer development remains poorly explored. During autophagic progression, we identified miR-449a as the most up-regulated miRNA. MiR-449a expression was low in the tumor parts of CRC patient specimens and inversely correlated with tumor stage and metastasis with the AUC (area under the curve) of 0.899 and 0.736 as well as poor overall survival rate, indicating that miR-449a has the potential to be a prognostic biomarker. In the same group of CRC specimens, low autophagic activity (low Beclin 1 expression and high p62 accumulation) was detected, which was significantly associated with miR-449a expression. Mechanistic studies disclosed that autophagy upregulates miR-449a expression through degradation of the coactivator p300 protein which acetylates the transcription factor Forkhead Box O1 (FoxO1). Unacetylated FoxO1 translocated to the nucleus and bound to the miR-449a promoter to drive gene expression. Either activation of autophagy by the inducer or overexpression of exogenous miR-449a decreases the expression of target gene LEF-1 and cyclin D1, which lead to decreased proliferation, colony formation, migration, and invasion of CRC cells. Autophagy-miR-449a-tartet genes mediated suppression of tumor formation was further confirmed in the xenograft mouse model. In conclusion, this study reveals a novel mechanism wherein autophagy utilizes miR-449a-LEF1-cyclin D1 axis to suppress CRC tumorigenesis. Our findings open a new avenue toward prognosis and treatment of CRC patients by manipulating autophagy-miR-449a axis.

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How autophagy controls the intestinal epithelial barrier

Cited by 180 publications

References 180 publications

Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans

Membrane protective role of autophagic machinery during infection of epithelial cells by Candida albicans

The Correlation Between MYO9B Gene Polymorphism and Inflammatory Bowel Disease in the Guangxi Zhuang Population

Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer

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