a Center for Biochemistry , University of Cologne , Cologne , Germany.
b Department of Dermatology, University of Cologne , Cologne , Germany.
Autophagy. 2018;14(3):465-486. doi: 10.1080/15548627.2017.1422850. Epub 2018 Mar 11.
TGFB1 (transforming growth factor beta 1) is a potent cytokine playing a driving role in development, fibrosis and cancer. It is synthesized as prodomain-growth factor complex that requires tethering to LTBP (latent transforming growth factor beta binding protein) for efficient secretion into the extracellular space. Upon release, this large latent complex is sequestered by anchorage to extracellular matrix (ECM) networks, from which the mature growth factor needs to be activated in order to reach its receptors and initiate signaling. Here, we uncovered a novel intracellular secretion pathway by which the latent TGFB1 complex reaches the plasma membrane and is released from fibroblasts, the key effector cells during tissue repair, fibrosis and in the tumor stroma. We show that secretion of latent TGFB1, but not of other selected cytokines or of bulk cargo, is regulated by fibroblast-ECM communication through ILK (integrin linked kinase) that restricts RHOA activity by interacting with ARHGAP26/GRAF1. Latent TGFB1 interacts with GORASP2/GRASP55 and is detected inside MAP1LC3-positive autophagosomal intermediates that are secreted by a RAB8A-dependent pathway. Interestingly, TGFB1 secretion is fully abrogated in human and murine fibroblasts and macrophages that lack key components of the autophagic machinery. Our data demonstrate an unconventional secretion mode of TGFB1 adding another level of control of its bioavailability and activity in order to effectively orchestrate cellular programs prone to dysregulation as seen in fibrosis and cancer.
TGFB1（转化生长因子β1）是一种有效的细胞因子，在发育、纤维化和癌症中发挥着驱动作用。它作为前导肽-生长因子复合物合成，需要与 LTBP（潜伏转化生长因子β结合蛋白）结合才能有效地分泌到细胞外空间。释放后，这个大型潜伏复合物通过锚定到细胞外基质（ECM）网络而被隔离，成熟的生长因子需要从这里被激活才能到达其受体并启动信号转导。在这里，我们揭示了一种新的细胞内分泌途径，通过该途径，潜伏的 TGFB1 复合物到达质膜并从成纤维细胞中释放出来，成纤维细胞是组织修复、纤维化和肿瘤基质中关键的效应细胞。我们表明，潜伏的 TGFB1 的分泌，而不是其他选定的细胞因子或大量货物的分泌，是通过成纤维细胞-ECM 通讯调节的，这种通讯通过整合素连接激酶（ILK）来限制 RHOA 的活性，ILK 通过与 ARHGAP26/GRAF1 相互作用来限制 RHOA 的活性。潜伏的 TGFB1 与 GORASP2/GRASP55 相互作用，并在 MAP1LC3 阳性自噬体中间物中被检测到，这些中间物是通过 RAB8A 依赖性途径分泌的。有趣的是，TGFB1 的分泌在缺乏自噬机制关键成分的人和鼠成纤维细胞和巨噬细胞中被完全阻断。我们的数据表明了 TGFB1 的一种非常规分泌模式，为其生物利用度和活性增加了另一个控制水平，以便有效地协调易失调的细胞程序，如纤维化和癌症中所见。
