Li Yujia, Fan Weiguo, Link Frederik, Wang Sai, Dooley Steven
Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Division of Gastroenterology and Hepatology, Stanford University, Stanford CA, USA.
JHEP Rep. 2021 Nov 18;4(2):100397. doi: 10.1016/j.jhepr.2021.100397. eCollection 2022 Feb.
Transforming growth factor-β (TGF-β) is a potent effector in the liver, which is involved in a plethora of processes initiated upon liver injury. TGF-β affects parenchymal, non-parenchymal, and inflammatory cells in a highly context-dependent manner. Its bioavailability is critical for a fast response to various insults. In the liver - and probably in other organs - this is made possible by the deposition of a large portion of TGF-β in the extracellular matrix as an inactivated precursor form termed latent TGF-β (L-TGF-β). Several matrisomal proteins participate in matrix deposition, latent complex stabilisation, and activation of L-TGF-β. Extracellular matrix protein 1 (ECM1) was recently identified as a critical factor in maintaining the latency of deposited L-TGF-β in the healthy liver. Indeed, its depletion causes spontaneous TGF-β signalling activation with deleterious effects on liver architecture and function. This review article presents the current knowledge on intracellular L-TGF-β complex formation, secretion, matrix deposition, and activation and describes the proteins and processes involved. Further, we emphasise the therapeutic potential of toning down L-TGF-β activation in liver fibrosis and liver cancer.
转化生长因子-β（TGF-β）是肝脏中的一种强效效应因子，参与肝脏损伤后引发的众多过程。TGF-β以高度依赖环境的方式影响实质细胞、非实质细胞和炎症细胞。其生物利用度对于快速应对各种损伤至关重要。在肝脏以及可能在其他器官中，这是通过将大部分TGF-β以一种称为潜伏性TGF-β（L-TGF-β）的无活性前体形式沉积在细胞外基质中来实现的。几种基质蛋白参与基质沉积、潜伏复合物稳定以及L-TGF-β的激活。细胞外基质蛋白1（ECM1）最近被确定为维持健康肝脏中沉积的L-TGF-β潜伏性的关键因素。事实上，其缺失会导致TGF-β信号通路的自发激活，对肝脏结构和功能产生有害影响。这篇综述文章介绍了目前关于细胞内L-TGF-β复合物形成、分泌、基质沉积和激活的知识，并描述了相关的蛋白质和过程。此外，我们强调了降低L-TGF-β激活在肝纤维化和肝癌中的治疗潜力。
