Calpain-14 and Its Association with Eosinophilic Esophagitis

Overview

Journal J Allergy Clin Immunol

Specialty Allergy & Immunology

Date 2017 Jan 30

PMID 28131390

Citations 46

Authors

Vladislav A Litosh

Mark Rochman

Jeffrey K Rymer

Aleksey Porollo

Leah C Kottyan

Marc E Rothenberg

Affiliations

Soon will be listed here.

Abstract

Calpains are a family of intracellular, calcium-dependent cysteine proteases involved in a variety of regulatory processes, including cytoskeletal dynamics, cell-cycle progression, signal transduction, gene expression, and apoptosis. These enzymes have been implicated in a number of disease processes, notably for this review involving eosinophilic tissue inflammation, such as eosinophilic esophagitis (EoE), a chronic inflammatory disorder triggered by allergic hypersensitivity to food and associated with genetic variants in calpain 14 (CAPN14). Herein we review the genetic, structural, and biochemical properties of CAPN14 and its gene product CAPN14, and its emerging role in patients with EoE. The CAPN14 gene is localized at chromosome 2p23.1-p21 and is most homologous to CAPN13 (36% sequence identity), which is located 365 kb downstream of CAPN14. Structurally, CAPN14 has classical calpain motifs, including a cysteine protease core. In comparison with other human calpains, CAPN14 has a unique expression pattern, with the highest levels in the upper gastrointestinal tract, particularly in the squamous epithelium of the esophagus. The CAPN14 gene is positioned in an epigenetic hotspot regulated by IL-13, a T2 cytokine with increased levels in patients with EoE that has been shown to be a mediator of the disease. CAPN14 induces disruptive effects on the esophageal epithelium by impairing epithelial barrier function in association with loss of desmoglein-1 expression and has a regulatory role in repairing epithelial changes induced by IL-13. Thus CAPN14 is a unique protease with distinct tissue-specific expression and function in patients with EoE and is a potential therapeutic target for EoE and related eosinophilic and allergic diseases.

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References

Low K, Partha S, Davies P, Campbell R . Allosteric inhibitors of calpains: Reevaluating inhibition by PD150606 and LSEAL. Biochim Biophys Acta. 2014; 1840(12):3367-73. DOI: 10.1016/j.bbagen.2014.08.014. View

Partha S, Ravulapalli R, Allingham J, Campbell R, Davies P . Crystal structure of calpain-3 penta-EF-hand (PEF) domain - a homodimerized PEF family member with calcium bound at the fifth EF-hand. FEBS J. 2014; 281(14):3138-49. DOI: 10.1111/febs.12849. View

Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View

Huang Y, de Morree A, van Remoortere A, Bushby K, Frants R, den Dunnen J . Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. Hum Mol Genet. 2008; 17(12):1855-66. PMC: 2900895. DOI: 10.1093/hmg/ddn081. View

Davis B, Stucke E, Khorki M, Litosh V, Rymer J, Rochman M . Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment. JCI Insight. 2016; 1(4):e86355. PMC: 4855700. DOI: 10.1172/jci.insight.86355. View

Berman H, Westbrook J, Feng Z, Gilliland G, Bhat T, Weissig H . The Protein Data Bank. Nucleic Acids Res. 1999; 28(1):235-42. PMC: 102472. DOI: 10.1093/nar/28.1.235. View

Kramerova I, Kudryashova E, Wu B, Germain S, Vandenborne K, Romain N . Mitochondrial abnormalities, energy deficit and oxidative stress are features of calpain 3 deficiency in skeletal muscle. Hum Mol Genet. 2009; 18(17):3194-205. PMC: 2722983. DOI: 10.1093/hmg/ddp257. View

Macqueen D, Wilcox A . Characterization of the definitive classical calpain family of vertebrates using phylogenetic, evolutionary and expression analyses. Open Biol. 2014; 4:130219. PMC: 4043111. DOI: 10.1098/rsob.130219. View

Porollo A, Adamczak R, Meller J . POLYVIEW: a flexible visualization tool for structural and functional annotations of proteins. Bioinformatics. 2004; 20(15):2460-2. DOI: 10.1093/bioinformatics/bth248. View

10.

Dear T, Boehm T . Identification and characterization of two novel calpain large subunit genes. Gene. 2001; 274(1-2):245-52. DOI: 10.1016/s0378-1119(01)00599-6. View

11.

Sleiman P, Wang M, Cianferoni A, Aceves S, Gonsalves N, Nadeau K . GWAS identifies four novel eosinophilic esophagitis loci. Nat Commun. 2014; 5:5593. PMC: 4238044. DOI: 10.1038/ncomms6593. View

12.

Hosfield C, Elce J, Davies P, Jia Z . Crystal structure of calpain reveals the structural basis for Ca(2+)-dependent protease activity and a novel mode of enzyme activation. EMBO J. 1999; 18(24):6880-9. PMC: 1171751. DOI: 10.1093/emboj/18.24.6880. View

13.

Kelley L, Mezulis S, Yates C, Wass M, Sternberg M . The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015; 10(6):845-58. PMC: 5298202. DOI: 10.1038/nprot.2015.053. View

14.

Moldoveanu T, Hosfield C, Lim D, Jia Z, Davies P . Calpain silencing by a reversible intrinsic mechanism. Nat Struct Biol. 2003; 10(5):371-8. DOI: 10.1038/nsb917. View

15.

Meyer W, Schoennagel B, Kacza J, Busche R, Hornickel I, Hewicker-Trautwein M . Keratinization of the esophageal epithelium of domesticated mammals. Acta Histochem. 2013; 116(1):235-42. DOI: 10.1016/j.acthis.2013.07.008. View

16.

Moldoveanu T, Hosfield C, Lim D, Elce J, Jia Z, Davies P . A Ca(2+) switch aligns the active site of calpain. Cell. 2002; 108(5):649-60. DOI: 10.1016/s0092-8674(02)00659-1. View

17.

Sherrill J, Rothenberg M . Genetic dissection of eosinophilic esophagitis provides insight into disease pathogenesis and treatment strategies. J Allergy Clin Immunol. 2011; 128(1):23-32. PMC: 3129465. DOI: 10.1016/j.jaci.2011.03.046. View

18.

Huang Y, Wang K . The calpain family and human disease. Trends Mol Med. 2001; 7(8):355-62. DOI: 10.1016/s1471-4914(01)02049-4. View

19.

Hornickel I, Kacza J, Schnapper A, Beyerbach M, Schoennagel B, Seeger J . Demonstration of substances of innate immunity in the esophageal epithelium of domesticated mammals: Part II--Defence mechanisms, including species comparison. Acta Histochem. 2009; 113(2):175-88. DOI: 10.1016/j.acthis.2009.09.008. View

20.

Sorimachi H, Hata S, Ono Y . Calpain chronicle--an enzyme family under multidisciplinary characterization. Proc Jpn Acad Ser B Phys Biol Sci. 2011; 87(6):287-327. PMC: 3153876. DOI: 10.2183/pjab.87.287. View