Spatial dynamics of IFITM1: a core component of the interferon-stimulated gene-resistance signature in glioma

Abstract

The IFITM1 protein is a key component of the Interferon-Stimulated Gene (ISG) network, which has been linked to treatment-resistant signatures in various cancers, including glioblastoma (GBM). Despite its impact, the mechanisms underlying IFITM1s role in cancer remain poorly understood. Here, we demonstrate that the spatial dynamics of IFITM1 localisation are highly context-dependent, particularly in GBM tissue. In the vasculature, IFITM1 is predominantly localised to the plasma membrane of endothelial cells. However, when present in a subset of cancer stem cells, IFITM1 adopts a distinct perinuclear location, where it co-localises with IFITM3 and is notably absent from the membrane. The spatial dynamics of IFITM1 localisation was investigated in patient-derived glioma stem cells (GSCs), primary endothelial cells and engineered cell lines. Endogenous IFITM1 localised primarily to assemblies in the perinuclear space, however loss of functional IFITM3 led to a shift in the distribution of the protein to a predominantly membrane location. In contrast, IFITM3 localisation was unaffected by the loss of IFITM1. The results were recapitulated by transient expression of IFITM1 or -3 into double knockout (DKO) GSCs and by using an engineered system where IFITM1 expression was IFN-independent. Co-expression studies demonstrate that IFITM3 is sufficient to localise IFITM1 to vesicle structures in the perinuclear space and that mutant forms of IFITM3 lead to retention of IFITM1 primarily at the plasma membrane. Our data highlights dynamic changes in the subcellular localisation of IFITM1 suggesting that distinct functions of this resistance factor may present a specific target for therapeutic intervention.