LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling

Science. 2019 May 10;364(6440):eaau0812. doi: 10.1126/science.aau0812.

Jin Huk Choi ^# ¹, Xue Zhong ^# ¹, William McAlpine ¹, Tzu-Chieh Liao ¹, Duanwu Zhang ¹, Beibei Fang ¹, Jamie Russell ¹, Sara Ludwig ¹, Evan Nair-Gill ¹, Zhao Zhang ¹, Kuan-Wen Wang ¹, Takuma Misawa ¹, Xiaoming Zhan ¹, Mihwa Choi ¹, Tao Wang ¹ ², Xiaohong Li ¹, Miao Tang ¹, Qihua Sun ¹, Liyang Yu ¹, Anne R Murray ¹, Eva Marie Y Moresco ¹, Bruce Beutler ³

Affiliations

1 Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. bruce.beutler@utsouthwestern.edu.
# Contributed equally.

PMID: 31073040 DOI: 10.1126/science.aau0812

Abstract

Precise control of Wnt signaling is necessary for immune system development. In this study, we detected severely impaired development of all lymphoid lineages in mice, resulting from an N-ethyl-N-nitrosourea-induced mutation in the limb region 1-like gene (Lmbr1l), which encodes a membrane-spanning protein with no previously described function in immunity. The interaction of LMBR1L with glycoprotein 78 (GP78) and ubiquitin-associated domain-containing protein 2 (UBAC2) attenuated Wnt signaling in lymphocytes by preventing the maturation of FZD6 and LRP6 through ubiquitination within the endoplasmic reticulum and by stabilizing "destruction complex" proteins. LMBR1L-deficient T cells exhibited hallmarks of Wnt/β-catenin activation and underwent apoptotic cell death in response to proliferative stimuli. LMBR1L has an essential function during lymphopoiesis and lymphoid activation, acting as a negative regulator of the Wnt/β-catenin pathway.

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