Substrate Stiffness-Driven Membrane Tension Modulates Vesicular Trafficking via Caveolin-1.
Substrate Stiffness-Driven Membrane Tension Modulates Vesicular Trafficking via Caveolin-1.
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DOI：
10.1021/acsnano.1c10534
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发表时间：
2022-03-22
期刊：
影响因子：
17.1
通讯作者：
Hernandez, Armando E. del Rio
中科院分区：
文献类型：
--
作者：
Lachowski, Dariusz;Matellan, Carlos;Gopal, Sahana;Cortes, Ernesto;Robinson, Benjamin K.;Saiani, Alberto;Miller, Aline F.;Stevens, Molly M.;Hernandez, Armando E. del Rio
肝纤维化是一种以细胞外基质（ECM）蛋白广泛沉积和交联为特征的疾病，在慢性肝损伤的情况下是特异性的。肝星状细胞（HSC）（纤维化的主要介质）对ECM重塑的失调导致ECM硬度升高，这驱动了慢性肝病如肝硬化和肝细胞癌的发展。基质金属蛋白酶组织抑制剂-1（TIMP-1）是调节ECM重塑的关键因素，它调节ECM成分的降解和周转。我们以前曾报道，一个刚性的，纤维化样基质可以影响TIMP-1的表达在蛋白质水平上在HSC，而不改变其mRNA的表达。虽然已知HSC对机械刺激高度敏感，但机械刺激在翻译后水平调节TIMP-1的机制仍不清楚。在这里，我们展示了一个机制的调节质膜张力的矩阵刚度。我们发现这种作用是由β1整合素/RhoA轴协调的，并以小窝蛋白-1和发动蛋白-2依赖的方式导致TIMP-1的胞吐和分泌升高。然后，我们表明，TIMP-1和小窝蛋白-1的表达增加，在肝硬化和肝细胞癌。这些病症与纤维化相关，并且这种作用可以在由封装在自组装多肽水凝胶中的肝星状细胞组成的3D纤维化模型中重现。这项工作将刚度依赖性膜张力定位为酶分泌和功能的关键调节因子，以及旨在调节慢性肝病中ECM重塑的治疗策略的潜在靶点。
Liver fibrosis, a condition characterized by extensive deposition and cross-linking of extracellular matrix (ECM) proteins, is idiosyncratic in cases of chronic liver injury. The dysregulation of ECM remodeling by hepatic stellate cells (HSCs), the main mediators of fibrosis, results in an elevated ECM stiffness that drives the development of chronic liver disease such as cirrhosis and hepatocellular carcinoma. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a key element in the regulation of ECM remodeling, which modulates the degradation and turnover of ECM components. We have previously reported that a rigid, fibrotic-like substrate can impact TIMP-1 expression at the protein level in HSCs without altering its mRNA expression. While HSCs are known to be highly susceptible to mechanical stimuli, the mechanisms through which mechanical cues regulate TIMP-1 at the post-translational level remain unclear. Here, we show a mechanism of regulation of plasma membrane tension by matrix stiffness. We found that this effect is orchestrated by the β1 integrin/RhoA axis and results in elevated exocytosis and secretion of TIMP-1 in a caveolin-1- and dynamin-2-dependent manner. We then show that TIMP-1 and caveolin-1 expression increases in cirrhosis and hepatocellular carcinoma. These conditions are associated with fibrosis, and this effect can be recapitulated in 3D fibrosis models consisting of hepatic stellate cells encapsulated in a self-assembling polypeptide hydrogel. This work positions stiffness-dependent membrane tension as a key regulator of enzyme secretion and function and a potential target for therapeutic strategies that aim at modulating ECM remodeling in chronic liver disease.
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影响因子：
19
作者：
Diz-Muñoz A;Fletcher DA;Weiner OD
通讯作者：
Weiner OD
影响因子：
6.2
作者：
Gao, Jie;Tang, Claire;Saiani, Alberto
通讯作者：
Saiani, Alberto
影响因子：
7.5
作者：
Del Pozo, Miguel A.;Lolo, Fidel-Nicolas;Echarri, Asier
通讯作者：
Echarri, Asier
影响因子：
4.3
作者：
Cox TR;Erler JT
通讯作者：
Erler JT
影响因子：
41.2
作者：
Chronopoulos, Antonios;Thorpe, Stephen D.;Hernandez, Armando E. del Rio
通讯作者：
Hernandez, Armando E. del Rio