Work

Mechanism of internalization of MDA-7/IL-24 protein and its cognate receptors following ligand-receptor docking

Year: 2019

Type: article

Abstract: // Anjan K. Pradhan 1 , Praveen Bhoopathi 1 , Sarmistha Talukdar 1 , Swadesh K. Das 1 , 2 , 3 , Luni Emdad 1 , 2 , 3 , Devanand Sarkar 1 , 2 , 3 , Andrei I. Ivanov 4 and Paul B. Fisher 1 , 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 Correspondence to: 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 ABSTRACT 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.27150