Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
J Biol Chem. 2011 Jun 17;286(24):21876-85. doi: 10.1074/jbc.M111.228262. Epub 2011 Apr 26.
Transforming growth factor (TGF)-β family proteins are synthesized as precursors that are cleaved to generate an active ligand. Previous studies suggest that TGF-β activity can be controlled by lysosomal degradation of both precursor proteins and ligands, but how these soluble proteins are trafficked to the lysosome is incompletely understood. The current studies show that sortilin selectively co-immunoprecipitates with the cleaved prodomain and/or precursor form of TGF-β family members. Furthermore, sortilin co-localizes with, and enhances accumulation of a nodal family member in the Golgi. Co-expression of sortilin with TGF-β family members leads to decreased accumulation of precursor proteins and cleavage products and this is attenuated by lysosomal, but not proteosomal inhibitors. In Xenopus embryos, overexpression of sortilin leads to a decrease in phospho-Smad2 levels and phenocopies loss of nodal signaling. Conversely, down-regulation of sortilin expression in HeLa cells leads to an up-regulation of endogenous bone morphogenic protein pathway activation, as indicated by an increase in phospho-Smad1/5/8 levels. Our results suggest that sortilin negatively regulates TGF-β signaling by diverting trafficking of precursor proteins to the lysosome during transit through the biosynthetic pathway.
转化生长因子 (TGF)-β 家族蛋白以前体形式合成，前体蛋白经切割后生成有活性的配体。先前的研究表明，TGF-β 活性可通过前体蛋白和配体的溶酶体降解来控制，但这些可溶性蛋白如何被转运到溶酶体尚不完全清楚。本研究表明，分选蛋白（sortilin）选择性地与 TGF-β 家族成员的裂解前导肽和/或前体形式共免疫沉淀。此外，分选蛋白与节点家族成员共定位，并增强其在高尔基体中的积累。分选蛋白与 TGF-β 家族成员共表达会导致前体蛋白和裂解产物的积累减少，而溶酶体抑制剂而非蛋白酶体抑制剂可减弱这种减少。在非洲爪蟾胚胎中，过表达分选蛋白会导致磷酸化 Smad2 水平降低，并表现出节点信号丢失的表型。相反，在 HeLa 细胞中下调分选蛋白的表达会导致内源性骨形态发生蛋白通路激活的上调，这表现为磷酸化 Smad1/5/8 水平的增加。我们的研究结果表明，分选蛋白通过在生物合成途径中运输前体蛋白到溶酶体来负调控 TGF-β 信号。
