The SERPINB4 Gene Mutation Identified in Twin Patients with Crohn's Disease Impaires the Intestinal Epithelial Cell Functions

Overview

Journal Sci Rep

Date 2025 Jan 21

PMID 39838210

Authors

Xiao-Mei Ouyang

Jun-Hui Lin

Ying Lin

Xian-Ling Zhao

Ya-Ni Huo

Lai-Ying Liang

Yong-Dong Huang

Gui-Jing Xie

Peng Mi

Zhen-Yu Ye

Bayasi Guleng

Affiliations

Soon will be listed here.

Abstract

Crohn's disease (CD) is a chronic inflammatory autoimmune disease of unknown etiology. To identify new targets related to the initiation of CD, we screened a pair of twins with CD, which is a rare phenomenon in the Chinese population, for genetic susceptibility factors. Whole-exome sequencing (WES) of these patients revealed a mutation in their SERPINB4 gene. Therefore, we studied a wider clinical cohort of patients with CD or ulcerous colitis (UC), healthy individuals, and those with a family history of CD for this mutation by Sanger sequencing. The single-nucleotide difference in the SERPINB4 gene, which was unique to the twin patients with CD, led to the substitution of lysine by a glutamic acid residue. Functional analysis indicated that this mutation of SERPINB4 inhibited the proliferation, colony formation, wound healing, and migration of intestinal epithelial cells (IECs). Furthermore, mutation of SERPINB4 induced apoptosis and activated apoptosis-related proteins in IECs, and a caspase inhibitor significantly reduced these effects. Transcriptome sequencing revealed that the expression of genes encoding proinflammatory proteins (IL1B, IL6, IL17, IL24, CCL2, and CXCR2) and key proteins in the immune response (S100A9, MMP3, and MYC) was significantly upregulated during SERPINB4 mutant-induced apoptosis. Thus, the heterozygous SERPINB4 gene mutation causes the dysfunction of IECs, which would disrupt the intestinal epithelial barrier and contribute to the development of intestinal inflammation. The activation of SERPINB4 might represent a novel therapeutic target for inflammatory bowel disease.

References

Hooper K, Barlow P, Henderson P, Stevens C . Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease. Inflamm Bowel Dis. 2018; 25(4):661-671. DOI: 10.1093/ibd/izy380. View

Lerner A, Neidhofer S, Reuter S, Matthias T . MMP3 is a reliable marker for disease activity, radiological monitoring, disease outcome predictability, and therapeutic response in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2019; 32(4):550-562. DOI: 10.1016/j.berh.2019.01.006. View

Wang G, Huang K, Tian Q, Guo Y, Liu C, Li Z . S100A9 aggravates early brain injury after subarachnoid hemorrhage via inducing neuroinflammation and inflammasome activation. iScience. 2024; 27(3):109165. PMC: 10901081. DOI: 10.1016/j.isci.2024.109165. View

Gatto M, Iaccarino L, Ghirardello A, Bassi N, Pontisso P, Punzi L . Serpins, immunity and autoimmunity: old molecules, new functions. Clin Rev Allergy Immunol. 2013; 45(2):267-80. DOI: 10.1007/s12016-013-8353-3. View

Iyer S, Gensollen T, Gandhi A, Oh S, Neves J, Collin F . Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses. Cell. 2018; 173(5):1123-1134.e11. PMC: 6119676. DOI: 10.1016/j.cell.2018.04.037. View

Roda G, Ng S, Kotze P, Argollo M, Panaccione R, Spinelli A . Crohn's disease. Nat Rev Dis Primers. 2020; 6(1):22. DOI: 10.1038/s41572-020-0156-2. View

Sivaprasad U, Kinker K, Ericksen M, Lindsey M, Gibson A, Bass S . SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis. J Invest Dermatol. 2014; 135(1):160-169. PMC: 4268075. DOI: 10.1038/jid.2014.353. View

Furey T, Sethupathy P, Sheikh S . Redefining the IBDs using genome-scale molecular phenotyping. Nat Rev Gastroenterol Hepatol. 2019; 16(5):296-311. PMC: 8311467. DOI: 10.1038/s41575-019-0118-x. View

Liu M, Wilson N, Hibbert J, Stiles J . STAT3 regulates MMP3 in heme-induced endothelial cell apoptosis. PLoS One. 2013; 8(8):e71366. PMC: 3742773. DOI: 10.1371/journal.pone.0071366. View

10.

Martini E, Krug S, Siegmund B, Neurath M, Becker C . Mend Your Fences: The Epithelial Barrier and its Relationship With Mucosal Immunity in Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol. 2017; 4(1):33-46. PMC: 5439240. DOI: 10.1016/j.jcmgh.2017.03.007. View

11.

Brand E, Klaassen M, Gacesa R, Vich Vila A, Ghosh H, de Zoete M . Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients. Gastroenterology. 2021; 160(6):1970-1985. DOI: 10.1053/j.gastro.2021.01.030. View

12.

Rathinam V, Chan F . Inflammasome, Inflammation, and Tissue Homeostasis. Trends Mol Med. 2018; 24(3):304-318. PMC: 6456255. DOI: 10.1016/j.molmed.2018.01.004. View

13.

Peterson L, Artis D . Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014; 14(3):141-53. DOI: 10.1038/nri3608. View

14.

Hu S, Uniken Venema W, Westra H, Vich Vila A, Barbieri R, Voskuil M . Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease. Nat Commun. 2021; 12(1):1122. PMC: 7892863. DOI: 10.1038/s41467-021-21458-z. View

15.

Ray R, Choi M, Zhang Z, Silverman G, Askew D, Mukherjee A . Uteroglobin suppresses SCCA gene expression associated with allergic asthma. J Biol Chem. 2005; 280(11):9761-4. DOI: 10.1074/jbc.C400581200. View

16.

Chen Y, Ouyang Y, Li Z, Wang X, Ma J . S100A8 and S100A9 in Cancer. Biochim Biophys Acta Rev Cancer. 2023; 1878(3):188891. DOI: 10.1016/j.bbcan.2023.188891. View

17.

Liu Z, Liu R, Gao H, Jung S, Gao X, Sun R . Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nat Genet. 2023; 55(5):796-806. PMC: 10290755. DOI: 10.1038/s41588-023-01384-0. View

18.

Holt-Danborg L, Vodopiutz J, Nonboe A, de Laffolie J, Skovbjerg S, Wolters V . SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase. Hum Mol Genet. 2018; 28(5):828-841. DOI: 10.1093/hmg/ddy394. View

19.

Turato C, Cannito S, Simonato D, Villano G, Morello E, Terrin L . SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity. Sci Rep. 2015; 5:17701. PMC: 4669520. DOI: 10.1038/srep17701. View

20.

Willms A, Schittek H, Rahn S, Sosna J, Mert U, Adam D . Impact of p53 status on TRAIL-mediated apoptotic and non-apoptotic signaling in cancer cells. PLoS One. 2019; 14(4):e0214847. PMC: 6448923. DOI: 10.1371/journal.pone.0214847. View