Intestinal epithelial cell polarity defects in disease: lessons from microvillus inclusion disease

Schneeberger, Kerstin; Roth, Stefan; Nieuwenhuis, Edward E. S.; Middendorp, Sabine

doi:10.1242/dmm.031088

Cited by 67 publications

(63 citation statements)

References 145 publications

(247 reference statements)

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“…As a proof of principle, we studied the dynamics of MVIs, the onset and elimination of which remain enigmatic. According to the 'combined' model of MVI onset (Schneeberger et al, 2018), the results of a recent paper using STXBP2 KO organoids (Mosa et al, 2018) and the results of the present study (Fig. 7), we showed that MVIs might arise by two main mechanisms: de novo nucleation in the cytoplasm or internalization of the PM.…”

Section: Discussionsupporting

confidence: 79%

“…For instance, whereas AP-1 is renowned for basolateral sorting in cultured cells (Gravotta et al, 2012), its crucial role in apical trafficking has been characterized in vivo in C. elegans and in mouse (Shafaq-Zadah et al, 2012;Zhang et al, 2012;Hase et al, 2013). Whereas the in vitro culture of intestinal organoids derived from patients with MVID or mice deficient in genes causing MVID (Schneeberger et al, 2018;Mosa et al, 2018;Wiegerinck et al, 2014) and the mutation of myoVb/goosepimples in zebrafish (Sidhaye et al, 2016) appear to reproduce most of the cellular and structural hallmarks of MVID, these models are not suitable for systematic studies. Conversely, the in vivo, easy-to-use and screening-amenable C. elegans model has been widely used to understand intestinal polarity mechanisms; however, single deletion of the orthologs of MVID-causing genes (i.e.…”

Section: Discussionmentioning

confidence: 99%

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A V0-ATPase-dependent apical trafficking pathway maintains the polarity of the intestinal absorptive membrane

et al. 2019

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Intestine function relies on the strong polarity of intestinal epithelial cells and the array of microvilli forming a brush border at their luminal pole. Combining a genetic RNA interference (RNAi) screen with in vivo super-resolution imaging in the Caenorhabditis elegans intestine, we found that the V0 sector of the vacuolar ATPase (V0-ATPase) controls a late apical trafficking step, involving Ras-related protein 11 (RAB-11) + endosomes and the N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) synaptosome-associated protein 29 (SNAP-29), and is necessary to maintain the polarized localization of both apical polarity modules and brush border proteins. We show that the V0-ATPase pathway also genetically interacts with glycosphingolipids and clathrin in enterocyte polarity maintenance. Finally, we demonstrate that silencing of the V0-ATPase fully recapitulates the severe structural, polarity and trafficking defects observed in enterocytes from individuals with microvillus inclusion disease (MVID) and use this new in vivo MVID model to follow the dynamics of microvillus inclusions. Thus, we describe a new function for V0-ATPase in apical trafficking and epithelial polarity maintenance and the promising use of the C. elegans intestine as an in vivo model to better understand the molecular mechanisms of rare genetic enteropathies.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

A V0-ATPase-dependent apical trafficking pathway maintains the polarity of the intestinal absorptive membrane

et al. 2019

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“…A delicate, single layer of columnar epithelial cells joined by tight junctions function to selectively regulate the movement of solutes and ions to produce a highly effective, yet remarkably dynamic barrier. 1 The intercellular tight junctional complexes restrict the movement of potential therapeutic agents with a molecular mass of greater than~500 Da between adjacent epithelial cells; the so-called paracellular route. Thus, macromolecules that cannot travel through the paracellular route may be absorbed at the luminal surface of the epithelium through receptor-and/or fluid phasemediated uptake mechanisms, but their fate typically involves recycling back into the lumen and/or routing to the lysosomal degradation pathway.…”

Section: Introductionmentioning

confidence: 99%

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

et al. 2020

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Cholix (Chx) is expressed by the intestinal pathogen Vibrio cholerae as a single chain of 634 amino acids (~70.7 kDa protein) that folds into three distinct domains, with elements of the second and third domains being involved in accessing the cytoplasm of nonpolarized cells and inciting cell death via ADP-ribosylation of elongation factor 2, respectively. In order to reach nonpolarized cells within the intestinal lamina propria, however, Chx must cross the polarized epithelial barrier in an intact form. Here, we provide in vitro and in vivo demonstrations that a nontoxic Chx transports across intestinal epithelium via a vesicular trafficking pathway that rapidly achieves vesicular apical to basal (A→B) transcytosis and avoids routing to lysosomes. Specifically, Chx traffics in apical endocytic Rab7 + vesicles and in basal exocytic Rab11 + vesicles with a transition between these domains occurring in the ER-Golgi intermediate compartment (ERGIC) through interactions with the lectin mannose-binding protein 1 (LMAN1) protein that undergoes an intracellular redistribution that coincides with the reorganization of COPI + and COPII + vesicular structures. Truncation studies demonstrated that domain I of Chx alone was sufficient to efficiently complete A→B transcytosis and capable of ferrying genetically conjoined human growth hormone (hGH). These studies provide evidence for a pathophysiological strategy where native Chx exotoxin secreted in the intestinal lumen by nonpandemic V. cholerae can reach nonpolarized cells within the lamina propria in an intact form by using a nondestructive pathway to cross in the intestinal epithelial that appears useful for oral delivery of biopharmaceuticals. One-Sentence Summary: Elements within the first domain of the Cholix exotoxin protein are essential and sufficient for the apical to basal transcytosis of this Vibrio cholerae-derived virulence factor across polarized intestinal epithelial cells.

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“…Interestingly, the route of application, apical versus the basolateral side of IECs, appears to influence DON-mediate changes in cell viability, as IPEC-J2 cell viability was more significantly affected when DON is applied to the basolateral side [157]. This differential susceptibility of apical and basolateral surfaces of IECs to DON exposure could be attributed to their biological and functional distinctions such as different protein and lipid compositions [172]. It could also result from the addition of the mucus produced by IPEC-J2 cells covering the apical side of epithelial monolayer [139] as an extra defense line against DON exposure.…”

Section: In-vitro Cell Culture Systemsmentioning

confidence: 99%

In-Vitro Cell Culture for Efficient Assessment of Mycotoxin Exposure, Toxicity and Risk Mitigation

Karrow

Shandilya

et al. 2020

Toxins

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Mycotoxins are toxic secondary fungal metabolites that commonly contaminate crops and food by-products and thus, animal feed. Ingestion of mycotoxins can lead to mycotoxicosis in both animals and humans, and at subclinical concentrations may affect animal production and adulterate feed and animal by-products. Mycotoxicity mechanisms of action (MOA) are largely unknown, and co-contamination, which is often the case, raises the likelihood of mycotoxin interactions. Mitigation strategies for reducing the risk of mycotoxicity are diverse and may not necessarily provide protection against all mycotoxins. These factors, as well as the species-specific risk of toxicity, collectively make an assessment of exposure, toxicity, and risk mitigation very challenging and costly; thus, in-vitro cell culture models provide a useful tool for their initial assessment. Since ingestion is the most common route of mycotoxin exposure, the intestinal epithelial barrier comprised of epithelial cells (IECs) and immune cells such as macrophages, represents ground zero where mycotoxins are absorbed, biotransformed, and elicit toxicity. This article aims to review different in-vitro IEC or co-culture models that can be used for assessing mycotoxin exposure, toxicity, and risk mitigation, and their suitability and limitations for the safety assessment of animal foods and food by-products.

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Intestinal epithelial cell polarity defects in disease: lessons from microvillus inclusion disease

Cited by 67 publications

References 145 publications

A V0-ATPase-dependent apical trafficking pathway maintains the polarity of the intestinal absorptive membrane

A V0-ATPase-dependent apical trafficking pathway maintains the polarity of the intestinal absorptive membrane

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

In-Vitro Cell Culture for Efficient Assessment of Mycotoxin Exposure, Toxicity and Risk Mitigation

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