Pradhan Anjan K, Bhoopathi Praveen, Talukdar Sarmistha, Das Swadesh K, Emdad Luni, Sarkar Devanand, Ivanov Andrei I, Fisher Paul B
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Oncotarget. 2019 Aug 20;10(49):5103-5117. doi: 10.18632/oncotarget.27150.
Melanoma differentiation associated gene-7 () is a member of the IL-10 family of cytokines, with ubiquitous direct and "bystander" tumor-selective killing properties. MDA-7/IL-24 protein binds distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2, IL-22R1/IL-20R1 and IL-22R1/IL-20R2. Recombinant MDA-7/IL-24 protein induces endogenous expression in a receptor-dependent manner; since A549 cells that lack a complete set of cognate receptors are not responsive to exogenous protein. The mechanism of MDA-7/IL-24 ligand-receptor biology is not well understood. We explored the interaction of MDA-7/IL-24 with its' receptors and the consequences of ligand-receptor docking. Using both pharmacological and genetic approaches we demonstrate that MDA-7/IL-24 internalization employs the clathrin-mediated endocytic pathway leading to degradation of receptors via the lysosomal/ubiquitin proteosomal pathway. This clathrin-mediated endocytosis is dynamin-dependent. This study resolves a novel mechanism of MDA-7/IL-24 protein "bystander" function, which involves receptor/protein-mediated internalization and receptor degradation.
黑色素瘤分化相关基因-7（）是白细胞介素-10细胞因子家族的成员，具有普遍存在的直接和“旁观者”肿瘤选择性杀伤特性。MDA-7/IL-24蛋白与不同的II型细胞因子异二聚体受体复合物IL-20R1/IL-20R2、IL-22R1/IL-20R1和IL-22R1/IL-20R2结合。重组MDA-7/IL-24蛋白以受体依赖的方式诱导内源性表达；因为缺乏完整同源受体的A549细胞对外源蛋白无反应。MDA-7/IL-24配体-受体生物学机制尚不清楚。我们探讨了MDA-7/IL-24与其受体的相互作用以及配体-受体对接的后果。使用药理学和遗传学方法，我们证明MDA-7/IL-24内化采用网格蛋白介导的内吞途径，导致受体通过溶酶体/泛素蛋白酶体途径降解。这种网格蛋白介导的内吞作用依赖于发动蛋白。本研究揭示了MDA-7/IL-24蛋白“旁观者”功能的一种新机制，该机制涉及受体/蛋白介导的内化和受体降解。
