Desmocollin-2 promotes intestinal mucosal repair by controlling integrin-dependent cell adhesion and migration

Flemming, Sven; Luissint, Anny‐Claude; Kusters, Dennis H. M.; Raya‐Sandino, Arturo; Fan, Shuling; Zhou, Dennis W.; Hasegawa, Mizuho; García-Hernández, Vicky; Garcı́a, Andrés J.; Parkos, Charles A.; Nusrat, Asma

doi:10.1091/mbc.e19-12-0692

Cited by 28 publications

(28 citation statements)

References 75 publications

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“…Interestingly, mice with permanent enterocyte‐specific knockout of Dsc2 did not show increased susceptibility to barrier dysfunction in DSS‐induced colitis. In contrast, in a model with an inducible conditional knockout of Dsc2 in enterocytes, mice exhibited impaired mucosal repair after biopsy‐induced colonic wounding and attenuated recovery from DSS‐induced colitis 78 . Therefore, it appears that in contrast to Dsg2, permanent loss of Dsc2 can be well compensated for, while acute loss of Dsc2 affects intestinal barrier function and especially mucosal wound healing.…”

Section: The Integrity Of Desmosomes Is Crucial To Maintain Intestinamentioning

confidence: 97%

“…75 On the contrary, it has been repeatedly shown that occludin is required for intact intestinal barrier function in various models, thus complicating our understanding of the specific role for occludin in IEB stability. 71,[76][77][78] Tricellulin, as its name suggests, is found where three or more cells meet and has also been implicated in the regulation of macromolecule flux. 79,80 Tricellulin is downregulated by Interleukin 13 receptor α2 in patients with UC, but not CD underlining its importance for intestinal barrier dysfunction at least for UC.…”

Section: Tj and Aj In The Intestinementioning

confidence: 99%

“…In contrast, in a model with an inducible conditional knockout of Dsc2 in enterocytes, mice exhibited impaired mucosal repair after biopsyinduced colonic wounding and attenuated recovery from DSS-induced colitis. 78 Therefore, it appears that in contrast to Dsg2, permanent loss of Dsc2 can be well compensated for, while acute loss of Dsc2 affects intestinal barrier function and especially mucosal wound healing. In vitro analyses using human intestinal cell lines after knockdown of Dsc2 demonstrated delayed epithelial cell migration and repair after scratch wounding.…”

Section: Desmosomes Is Crucial To Maintain Intestinal Barrier Functiomentioning

confidence: 99%

“…This was associated with reduced cell-matrix traction forces, decreased levels of integrin β 1 and β 4 and altered activity of the small GTPase Rap1. 78…”

Section: Desmosomes Is Crucial To Maintain Intestinal Barrier Functiomentioning

confidence: 99%

“…Instead, a role for occludin in regulating apoptosis was proposed 75 . On the contrary, it has been repeatedly shown that occludin is required for intact intestinal barrier function in various models, thus complicating our understanding of the specific role for occludin in IEB stability 71,76‐78 . Tricellulin, as its name suggests, is found where three or more cells meet and has also been implicated in the regulation of macromolecule flux 79,80 .…”

Section: Tj and Aj In The Intestinementioning

confidence: 99%

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Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

2020

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Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and Ulcerative colitis (UC) have a complex and multifactorial pathogenesis which is incompletely understood. A typical feature closely associated with clinical symptoms is impaired intestinal epithelial barrier function. Mounting evidence suggests that desmosomes, which together with tight junctions (TJ) and adherens junctions (AJ) form the intestinal epithelial barrier, play a distinct role in IBD pathogenesis. This is based on the finding that desmoglein (Dsg) 2, a cadherin‐type adhesion molecule of desmosomes, is required for maintenance of intestinal barrier properties both in vitro and in vivo, presumably via Dsg2‐mediated regulation of TJ. Mice deficient for intestinal Dsg2 show increased basal permeability and are highly susceptible to experimental colitis. In several cohorts of IBD patients, intestinal protein levels of Dsg2 are reduced and desmosome ultrastructure is altered suggesting that Dsg2 is involved in IBD pathogenesis. In addition to its adhesive function, Dsg2 contributes to enterocyte cohesion and intestinal barrier function. Dsg2 is also involved in enterocyte proliferation, barrier differentiation and induction of apoptosis, in part by regulation of p38MAPK and EGFR signalling. In IBD, the function of Dsg2 appears to be compromised via p38MAPK activation, which is a critical pathway for regulation of desmosomes and is associated with keratin phosphorylation in IBD patients. In this review, the current findings on the role of Dsg2 as a novel promising target to prevent loss of intestinal barrier function in IBD patients are discussed.

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Section: The Integrity Of Desmosomes Is Crucial To Maintain Intestinamentioning

confidence: 97%

Section: Tj and Aj In The Intestinementioning

confidence: 99%

Section: Desmosomes Is Crucial To Maintain Intestinal Barrier Functiomentioning

confidence: 99%

“…This was associated with reduced cell-matrix traction forces, decreased levels of integrin β 1 and β 4 and altered activity of the small GTPase Rap1. 78…”

Section: Desmosomes Is Crucial To Maintain Intestinal Barrier Functiomentioning

confidence: 99%

Section: Tj and Aj In The Intestinementioning

confidence: 99%

See 3 more Smart Citations

Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

2020

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Androgen downregulates desmocollin‐2 in association with induction of mesenchymal transition of breast MDA‐MB‐453 cancer cells

et al. 2021

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Desmosomes are cellular structures that are critical in cell-cell adhesion and in maintaining tissue architecture. Changes in the expression of desmocollin-2 (DSC2) have been noted during tumor progression into an invasive phenotype and as cells undergo epithelial-mesenchymal transition. We have previously reported that breast MDA-MB-453 cancer cells, a luminal androgen receptor (AR) model of triple-negative breast cancer, acquire mesenchymal features when treated with the AR agonist, dihydrotestosterone (DHT). We have therefore investigated androgen regulation of the expression and cellular localization of DSC2 in MDA-MB-453 cells. Treatment of the cells with DHT resulted in a dose-dependent reduction in DSC2 protein levels and dispersion of its membrane localization concomitant with AR-and β-cateninmediated mesenchymal transition of cells. A significant correlation was revealed between decreased expression of AR and increased expression of DSC2 in patient samples. In addition, whereas lower expression of AR was associated with a reduced overall and recurrence-free survival of breast cancer patients, higher expression of DSC2 was found in invasive breast tumors than in normal breast cells and was correlated with lower patient survival. Upon knocking down DSC2, the cells became elongated, mesenchymal-like, and slightly, but insignificantly, more migratory. The addition of DHT further stimulated cell elongation and migration. DSC2 siRNAtransfected cells reverted to a normal epithelial morphology upon inhibition of β-catenin. These results highlight the role of DSC2 in maintaining the epithelial morphology of MDA-MB-453 cells and the negative regulation of the desmosomal protein by DHT during stimulation of the androgen-induced, β-catenin-mediated mesenchymal transition of the cells.

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The keratin-desmosome scaffold of internal epithelia in health and disease – The plot is thickening

Toivola,

Polari,

Schwerd

et al. 2024

Current Opinion in Cell Biology

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Desmocollin-2 promotes intestinal mucosal repair by controlling integrin-dependent cell adhesion and migration

Abstract: We report a key role for Dsc2 in simple epithelial cell migration and mucosal wound healing in vivo using newly generated mice with inducible conditional knockdown of Dsc2 in intestinal epithelial cells ( Villin-CreERT2; Dsc2fl/fl).

Cited by 28 publications

References 75 publications

Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

Androgen downregulates desmocollin‐2 in association with induction of mesenchymal transition of breast MDA‐MB‐453 cancer cells

The keratin-desmosome scaffold of internal epithelia in health and disease – The plot is thickening

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