» Articles » PMID: 33596089

Regulation of Intestinal Epithelial Intercellular Adhesion and Barrier Function by Desmosomal Cadherin Desmocollin-2

Abstract

The role of desmosomal cadherin desmocollin-2 (Dsc2) in regulating barrier function in intestinal epithelial cells (IECs) is not well understood. Here, we report the consequences of silencing Dsc2 on IEC barrier function in vivo using mice with inducible intestinal-epithelial-specific knockdown (KD) (). While the small intestinal gross architecture was maintained, loss of epithelial Dsc2 influenced desmosomal plaque structure, which was smaller in size and had increased intermembrane space between adjacent epithelial cells. Functional analysis revealed that loss of Dsc2 increased intestinal permeability in vivo, supporting a role for Dsc2 in the regulation of intestinal epithelial barrier function. These results were corroborated in model human IECs in which Dsc2 KD resulted in decreased cell-cell adhesion and impaired barrier function. It is noteworthy that Dsc2 KD cells exhibited delayed recruitment of desmoglein-2 (Dsg2) to the plasma membrane after calcium switch-induced intercellular junction reassembly, while E-cadherin accumulation was unaffected. Mechanistically, loss of Dsc2 increased desmoplakin (DP I/II) protein expression and promoted intermediate filament interaction with DP I/II and was associated with enhanced tension on desmosomes as measured by a Dsg2-tension sensor. In conclusion, we provide new insights on Dsc2 regulation of mechanical tension, adhesion, and barrier function in IECs.

Citing Articles

Duodenal Organoids From Metabolic Dysfunction-Associated Steatohepatitis Patients Exhibit Absorptive and Barrier Alterations.

Hadefi A, Leprovots M, Dinsart G, Marefati M, Vermeersch M, Monteyne D Gastro Hep Adv. 2025; 4(4):100599.

PMID: 39996241 PMC: 11849614. DOI: 10.1016/j.gastha.2024.100599.


STARD7 maintains intestinal epithelial mitochondria architecture, barrier integrity, and protection from colitis.

Uddin J, Sharma A, Wu D, Tomar S, Ganesan V, Reichel P JCI Insight. 2024; 9(22).

PMID: 39576011 PMC: 11601949. DOI: 10.1172/jci.insight.172978.


The centrosomal protein FGFR1OP controls myosin function in murine intestinal epithelial cells.

Trsan T, Peng V, Krishna C, Ohara T, Beatty W, Sudan R Dev Cell. 2024; 59(18):2460-2476.e10.

PMID: 38942017 PMC: 11421975. DOI: 10.1016/j.devcel.2024.06.001.


Microbial Signatures in COVID-19: Distinguishing Mild and Severe Disease via Gut Microbiota.

Galeeva J, Fedorov D, Starikova E, Manolov A, Pavlenko A, Selezneva O Biomedicines. 2024; 12(5).

PMID: 38790958 PMC: 11118803. DOI: 10.3390/biomedicines12050996.


Intestinal Barrier Dysfunction and Gut Microbiota in Non-Alcoholic Fatty Liver Disease: Assessment, Mechanisms, and Therapeutic Considerations.

Long C, Zhou X, Xia F, Zhou B Biology (Basel). 2024; 13(4).

PMID: 38666855 PMC: 11048184. DOI: 10.3390/biology13040243.


References
1.
Burdett I, Sullivan K . Desmosome assembly in MDCK cells: transport of precursors to the cell surface occurs by two phases of vesicular traffic and involves major changes in centrosome and Golgi location during a Ca(2+) shift. Exp Cell Res. 2002; 276(2):296-309. DOI: 10.1006/excr.2002.5509. View

2.
Nekrasova O, Green K . Desmosome assembly and dynamics. Trends Cell Biol. 2013; 23(11):537-46. PMC: 3913269. DOI: 10.1016/j.tcb.2013.06.004. View

3.
Albrecht L, Zhang L, Shabanowitz J, Purevjav E, Towbin J, Hunt D . GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin-cytoskeleton dynamics. J Cell Biol. 2015; 208(5):597-612. PMC: 4347645. DOI: 10.1083/jcb.201406020. View

4.
Ingber D . Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J Cell Sci. 1993; 104 ( Pt 3):613-27. DOI: 10.1242/jcs.104.3.613. View

5.
Todorovic V, Koetsier J, Godsel L, Green K . Plakophilin 3 mediates Rap1-dependent desmosome assembly and adherens junction maturation. Mol Biol Cell. 2014; 25(23):3749-64. PMC: 4230782. DOI: 10.1091/mbc.E14-05-0968. View