LSR targets YAP to modulate intestinal Paneth cell differentiation

Yanan An; Chao Wang; Baozhen Fan; Ziqi Wang; Ying Li; Feng Kong; Chengjun Zhou; Zhang Cao; Mingxia Wang; Hui Sun; Shengtian Zhao; Yongfeng Gong

doi:10.1016/j.celrep.2023.113118

LSR targets YAP to modulate intestinal Paneth cell differentiation

Cell Rep. 2023 Sep 26;42(9):113118. doi: 10.1016/j.celrep.2023.113118. Epub 2023 Sep 12.

Authors

Yanan An¹, Chao Wang², Baozhen Fan³, Ziqi Wang⁴, Ying Li⁴, Feng Kong⁵, Chengjun Zhou⁶, Zhang Cao⁷, Mingxia Wang⁴, Hui Sun⁴, Shengtian Zhao⁸, Yongfeng Gong⁹

Affiliations

¹ Department of Physiology, Binzhou Medical University, Yantai, Shandong, China; Shandong Engineering Research Center of Molecular Medicine for Renal Diseases, Yantai, Shandong, China.
² Department of Urology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
³ Department of Urology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China.
⁴ Department of Physiology, Binzhou Medical University, Yantai, Shandong, China.
⁵ Shandong Provincial Engineering Laboratory of Urologic Tissue Reconstruction, Jinan, Shandong, China; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
⁶ Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
⁷ Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong, China.
⁸ Department of Urology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China; Shandong Provincial Engineering Laboratory of Urologic Tissue Reconstruction, Jinan, Shandong, China; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: zhaoshengtian@sdu.edu.cn.
⁹ Department of Physiology, Binzhou Medical University, Yantai, Shandong, China; Shandong Engineering Research Center of Molecular Medicine for Renal Diseases, Yantai, Shandong, China. Electronic address: ygong@bzmc.edu.cn.

PMID: 37703178
DOI: 10.1016/j.celrep.2023.113118

Abstract

Lipolysis-stimulated lipoprotein receptor (LSR) is a multi-functional protein that is best known for its roles in assembly of epithelial tricellular tight junctions and hepatic clearance of lipoproteins. Here, we investigated whether LSR contributes to intestinal epithelium homeostasis and pathogenesis of intestinal disease. By using multiple conditional deletion mouse models and ex vivo cultured organoids, we find that LSR elimination in intestinal stem cells results in the disappearance of Paneth cells without affecting the differentiation of other cell lineages. Mechanistic studies reveal that LSR deficiency increases abundance of YAP by modulating its phosphorylation and proteasomal degradation. Using gain- and loss-of-function studies, we show that LSR protects against necrotizing enterocolitis through enhancement of Paneth cell differentiation in small-intestinal epithelium. Thus, this study identifies LSR as an upstream negative regulator of YAP activity, an essential factor for Paneth cell differentiation, and a potential therapeutic target for necrotizing enterocolitis.

Keywords: CP: Cell biology; CP: Stem cell research; LSR; Paneth cell; YAP; intestinal stem cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Enterocolitis, Necrotizing*
Intestinal Mucosa / metabolism
Intestines
Mice
Paneth Cells / metabolism
Receptors, Lipoprotein* / metabolism

Substances

Receptors, Lipoprotein