LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling

Jin Huk Choi, Xue Zhong, William McAlpine, Tzu Chieh Liao, Duan-Wu Zhang Ph.D., Beibei Fang, Jamie Russell, Sara Ludwig, Evan Nair-Gill, Zhao Zhang, Kuan Wen Wang, Takuma Misawa, Xiaoming Zhan, Mihwa Choi, Tao Wang, Xiaohong Li, Miao Tang, Qihua Sun, Liyang Yu, Anne R. MurrayEvamarie Y. Moresco, Bruce Beutler

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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.

Original languageEnglish (US)
Article numbereaau0812
JournalScience
Volume364
Issue number6440
DOIs
Publication statusPublished - Jan 1 2019

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Choi, J. H., Zhong, X., McAlpine, W., Liao, T. C., Zhang Ph.D., D-W., Fang, B., ... Beutler, B. (2019). LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling. Science, 364(6440), [eaau0812]. https://doi.org/10.1126/science.aau0812