NYMC Faculty Publications

Interferon-α-Induced Cytoplasmic MxA Structures in Hepatoma Huh7 and Primary Endothelial Cells

Journal Title

Contemporary Oncology

First Page

86

Last Page

94

Document Type

Article

Publication Date

January 2018

Department

Cell Biology and Anatomy

Abstract

Aim of the study: Interferon (IFN)-alpha is now established as a treatment modality in various human cancers. The IFN-alpha-inducible human "myxovirus resistance protein A" (MxA) is a cytoplasmic dynamin-family large GTPase primarily characterized for its broad-spectrum antiviral activity and, more recently, for its anti-tumor and anti-metastasis effects. We characterized the association of IFN-alpha-induced MxA with cytoplasmic structures in human Huh7 cancer cells and in primary endothelial cells. Material and methods: We re-evaluated the long-standing inference that MxA associated with the smooth ER using double-label immunofluorescence techniques and the ER structural protein RTN4 as a marker for smooth ER in IFN-alpha-treated cells. We also evaluated the relationship of exogenously expressed HA-MxA and GFP-MxA with mitochondria, and characterized cytoplasmic GFP-MxA structures using correlated light and electron microscopy (CLEM). Results and conclusions: We discovered that IFN-alpha-induced endogenous MxA associated with variably-sized endosome-like and reticular cytoplasmic structures which were distinct from the ER. Thin-section EM studies of GFP-MxA expressing Huh7 cells showed that GFP-MxA formed variably-sized clusters of vesiculotubular elements to form endosome-like "MxA bodies". Many of these clusters stretched out alongside cytoskeletal elements to give the appearance of a cytoplasmic "MxA reticulum". This MxA meshwork was distinct from but adjacent to mitochondria. GFP-MxA expressing Huh7 cells showed reduced MitoTracker uptake and swollen mitochondria by thin-section EM. The new data identify cytoplasmic MxA structures as novel organelles, and suggest cross-talk between MxA structures and mitochondria that might account for the increased anti-tumoral efficacy of IFN-alpha combined with ligands that activate other pattern-sensing receptor pathways.

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