PDF(Pubmed)
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.
摘要：
动力蛋白胞质1轻中间链1（LIC1，DYNC1LI1）是动力蛋白运动复合物的核心亚基。LIC1亚基还与各种货物衔接子相互作用以调节Rab介导的内体再循环和溶酶体降解。预测该基因的缺陷会改变动力蛋白的运动功能，Rab绑定功能，和细胞质货物贩运。这里,我们已经确定了一个dync1li1斑马鱼突变体，在外显子12/13剪接受体位点有一个过早的终止密码子，显示血管生成增加。体外，缺乏LIC1的人内皮细胞在促血管生成受体VEGFR2，SRC磷酸化的细胞表面水平增加，和Rab11介导的内体再循环。在体内,组成型活性Rab11a的内皮特异性表达导致过度血管生成，类似于dync1li1突变体。增加的血管生成也是明显的斑马鱼有突变的rilpl1/2，促进Rab对接Lic1介导溶酶体靶向的衔接蛋白。这些发现表明LIC1和Rab-衔接蛋白RILPL1和2通过促进含VEGFR2的再循环内体的降解来限制血管生成。破坏LIC1-和RILPL1/2介导的溶酶体靶向增加Rab11介导的再循环内体活性，促进过度的SRC信号和血管生成。
