Oncotarget

Research Papers:

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

Anjan K. Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Swadesh K. Das, Luni Emdad, Devanand Sarkar, Andrei I. Ivanov and Paul B. Fisher _

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Oncotarget. 2019; 10:5103-5117. https://doi.org/10.18632/oncotarget.27150

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Abstract

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

Correspondence to:

Paul B. Fisher,email: paul.fisher@vcuhealth.org

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.


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