Angiogenesis is limited by LIC1-mediated lysosomal trafficking.

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Dymonn Johnson, Sarah Colijn, Jahmiera Richee, Joseph Yano, Margaret Burns, Andrew E Davis, Van N Pham, Amra Saric, Akansha Jain, Ying Yin, Daniel Castranova, Mariana Melani, Misato Fujita, Stephanie Grainger, Juan S Bonifacino, Brant M Weinstein, Amber N Stratman
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引用次数: 0

Abstract

Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, DYNC1LI1) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified a dync1li1 zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis. In vitro, LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling. In vivo, endothelial-specific expression of constitutively active Rab11a leads to excessive angiogenesis, similar to the dync1li1 mutants. Increased angiogenesis is also evident in zebrafish harboring mutations in rilpl1/2, the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.

血管生成受到 LIC1 介导的溶酶体贩运的限制。
动力蛋白胞质 1 轻中间链 1(LIC1,DYNC1LI1)是动力蛋白运动复合体的核心亚基。LIC1 亚基还与各种货物适配体相互作用,调节 Rab 介导的内体循环和溶酶体降解。据预测,该基因缺陷会改变动力蛋白的运动功能、Rab结合能力和细胞质货物运输。在这里,我们发现了一种 dync1li1 斑马鱼突变体,该突变体在外显子 12/13 拼接接受位点处含有一个过早终止密码子,显示血管生成增加。在体外,LIC1缺陷的人内皮细胞显示促血管生成受体VEGFR2的细胞表面水平、SRC磷酸化和Rab11介导的内体循环增加。在体内,内皮特异性表达组成型活性 Rab11a 会导致过度的血管生成,这与 dync1li1 突变体类似。在携带 rilpl1/2 突变的斑马鱼中,血管生成的增加也很明显,rilpl1/2 是一种适配蛋白,能促进 Rab 与 Lic1 的对接,从而介导溶酶体靶向。这些发现表明,LIC1 和 Rab 适配蛋白 RILPL1 和 2 通过促进含有 VEGFR2 的循环内体降解来限制血管生成。破坏LIC1和RILPL1/2介导的溶酶体靶向会增加Rab11介导的循环内体活性,促进过度的SRC信号传导和血管生成。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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