Mechanism of internalization of MDA-7/IL-24 protein and its cognate receptors following ligand-receptor docking
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Anjan K. Pradhan1, Praveen Bhoopathi1, Sarmistha Talukdar1, Swadesh K. Das1,2,3, Luni Emdad1,2,3, Devanand Sarkar1,2,3, Andrei I. Ivanov4 and Paul B. Fisher1,2,3
1 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
2 VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
3 VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
4 Department of Inflammation and Immunity, Lerner Research Institute at Cleveland Clinic, Cleveland, OH, USA
|Paul B. Fisher,||email:||[email protected]|
Keywords: MDA-7/Interleukin-24; Interleukin receptor; recombinant protein
Received: June 21, 2019 Accepted: July 29, 2019 Published: August 20, 2019
Melanoma differentiation associated gene-7 (mda-7/IL-24) 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 mda-7/IL-24 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.
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