NYMC Faculty Publications


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

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January 2018


Cell Biology and Anatomy


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.