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
Affiliations
Yanan An
Department of Physiology, Binzhou Medical University, Yantai, Shandong, China; Shandong Engineering Research Center of Molecular Medicine for Renal Diseases, Yantai, Shandong, China
Chao Wang
Department of Urology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Baozhen Fan
Department of Urology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
Ziqi Wang
Department of Physiology, Binzhou Medical University, Yantai, Shandong, China
Ying Li
Department of Physiology, Binzhou Medical University, Yantai, Shandong, China
Feng Kong
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
Chengjun Zhou
Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Zhang Cao
Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong, China
Mingxia Wang
Department of Physiology, Binzhou Medical University, Yantai, Shandong, China
Hui Sun
Department of Physiology, Binzhou Medical University, Yantai, Shandong, China
Shengtian Zhao
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; Corresponding author
Yongfeng Gong
Department of Physiology, Binzhou Medical University, Yantai, Shandong, China; Shandong Engineering Research Center of Molecular Medicine for Renal Diseases, Yantai, Shandong, China; Corresponding author
Summary: 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.
