Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Matrix Biol. 2022 Jun;110:60-75. doi: 10.1016/j.matbio.2022.04.004. Epub 2022 Apr 19.
LTBP1 is a large extracellular matrix protein and an associated ligand of fibrillin-microfibrils. Knowledge of LTBP1 functions is largely limited to its role in targeting and sequestering TGFβ growth factors within the extracellular matrix, thereby regulating their bioavailability. However, the recent description of a wide spectrum of phenotypes in multiple tissues in patients harboring LTBP1 pathogenic variants suggests a multifaceted role of the protein in the homeostasis of connective tissues. To better understand the human pathology caused by LTBP1 deficiency it is important to investigate its functional role in extracellular matrix formation. In this study, we show that LTBP1 coordinates the incorporation of fibrillin-1 and -2 into the extracellular matrix in vitro. We also demonstrate that this function is differentially exerted by the two isoforms, the short and long forms of LTBP1. Thereby our findings uncover a novel TGFβ-independent LTBP1 function potentially contributing to the development of connective tissue disorders.
LTBP1 是一种大型细胞外基质蛋白，也是原纤维蛋白-微纤维的相关配体。目前对 LTBP1 功能的了解主要局限于其在将 TGFβ 生长因子靶向和隔离到细胞外基质内以调节其生物利用度方面的作用。然而，最近在携带 LTBP1 致病性变异的患者的多种组织中描述了广泛的表型，提示该蛋白在结缔组织的动态平衡中具有多方面的作用。为了更好地了解 LTBP1 缺乏引起的人类病理学，研究其在细胞外基质形成中的功能作用非常重要。在这项研究中，我们表明 LTBP1 在体外协调原纤维蛋白-1 和 -2 掺入细胞外基质。我们还证明了这一功能由两种同工型，即 LTBP1 的短型和长型，以不同的方式发挥作用。因此，我们的发现揭示了一种新的 TGFβ 非依赖性 LTBP1 功能，可能有助于结缔组织疾病的发展。
