Myoferlin contributes to invasiveness of human T-cell leukemia virus type 1-infected T cells

The retrovirus human T-cell leukemia virus type 1 (HTLV-1) predominantly infects CD4⁺ T cells in vivo. Two of the primary diseases caused by HTLV-1 infection are an aggressive leukemia designated adult T-cell leukemia (ATL) and a progressive neurodegenerative disease known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). For both diseases, an enhanced infiltration capacity of the HTLV-1⁺ T cells contributes to pathogenesis. This phenotype arises from changes in gene expression elicited by viral proteins. We recently reported that the viral protein, HBZ, activates expression of myoferlin (MyoF), which is overexpressed in several epithelial cancers where it promotes tumor cell metastasis. To test whether MyoF also contributes to the infiltration capacity of HTLV-1⁺ T cells, we performed in vitro adhesion, migration, and invasion assays using HTLV-1-transformed T cells. MyoF knockdown or inhibition in these cells reduced their adhesion to an endothelial cell monolayer and similarly diminished their invasion properties. RNA-seq analysis showed that knockdown of MyoF in HTLV-1-infected cells reduced expression of several genes involved in these processes, among which was COTL1 (coactosin-like protein 1). COTL1 binds and stabilizes filamentous actin and has been reported to both promote and inhibit tumor cell metastasis. In HTLV-1-infected cells, the effect of knocking down COTL1 was restricted to reducing cell invasion through a reconstituted basement membrane. From these results, we propose that MyoF contributes to the infiltration capacity of HTLV-1⁺ T cells, in part, by affecting gene expression, with MyoF-enforced expression of COTL1 specifically facilitating HTLV-1⁺ T-cell migration through extracellular matrices. IMPORTANCECD4⁺ T cells infected with human T-cell leukemia virus type 1 (HTLV-1) display an enhanced ability to infiltrate into tissues and organs, sometimes leading to pathological effects in patients infected with the virus. We provide evidence that abnormal expression of the cellular protein myoferlin (MyoF) in HTLV-1-infected T cells contributes to this phenotype, in part, by directing changes in the expression of other cellular genes. One gene on which MyoF produces a positive effect on expression was found to be COTL1, which encodes the F-actin-binding protein, coactosin-like protein 1. Our results indicate that COTL1 plays a specific role in the migration of HTLV-1-infected T cells through extracellular matrices, which is a critical step in the process of tissue infiltration.