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. [email protected].
  • # 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.