Department of Radiation Sciences, Oncology, Umeå University, SE-90187, Umeå, Sweden.
Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skane University Hospital, Malmo, Sweden.
Commun Biol. 2021 Jan 19;4(1):90. doi: 10.1038/s42003-020-01613-w.
Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-β) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease.
富含亮氨酸重复和免疫球蛋白样结构域（LRIG）蛋白被认为是生长因子信号转导的调节因子；然而，哺乳动物 LRIG1、LRIG2 和 LRIG3 之间可能存在冗余，这阻碍了它们生理功能的详细阐明。在这里，我们表明 Lrig 缺失的小鼠胚胎成纤维细胞（MEFs）在脂肪生成和骨形态发生蛋白（BMP）信号转导方面存在缺陷。相比之下，Lrig 缺失细胞中的转化生长因子-β（TGF-β）和受体酪氨酸激酶（RTK）信号似乎没有改变。LRIG1 或 LRIG3 的异位表达可挽救 BMP 信号缺陷，但 LRIG2 的表达则不能。秀丽隐杆线虫中突变的 LRIG/sma-10 变体也表现出脂质储存缺陷。人类 LRIG1 变体与体重指数（BMI）增加强烈相关，但可预防 2 型糖尿病；这些影响可能是通过改变脂肪细胞形态介导的。这些结果表明，LRIG 蛋白是脂质代谢和 BMP 信号转导的进化保守调节因子，与人类疾病有关。
