A critical role for IL-17RB signaling in HTLV-1 tax-induced NF-κB activation and T-cell transformation

• Published in: PLoS pathogens 2014-10, Vol.10 (10), p.e1004418
• Main Authors: Lavorgna, Alfonso, Matsuoka, Masao, Harhaj, Edward William
• Format: Article
• Language: English
• Subjects: Biology and Life Sciences; Cell research; Cell Transformation, Neoplastic - metabolism; Cellular signal transduction; Gene Expression Regulation - physiology; Gene Products, tax - metabolism; Health aspects; Host-parasite relationships; Human T-lymphotropic virus 1 - metabolism; Humans; Interleukin-17 - metabolism; Interleukins; Medicine and Health Sciences; NF-kappa B - metabolism; Receptors, Interleukin-17 - metabolism; Retroviruses; Signal Transduction - physiology; T cells; T-Lymphocytes - cytology; Virus research
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004418

Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia (ATL) and the neuroinflammatory disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein functions as a potent viral oncogene that constitutively activates the NF-κB transcription factor to transform T cells; however, the underlying mechanisms remain obscure. Here, using next-generation RNA sequencing we identified the IL-25 receptor subunit IL-17RB as an aberrantly overexpressed gene in HTLV-1 immortalized T cells. Tax induced the expression of IL-17RB in an IκB kinase (IKK) and NF-κB-dependent manner. Remarkably, Tax activation of the canonical NF-κB pathway in T cells was critically dependent on IL-17RB expression. IL-17RB and IL-25 were required for HTLV-1-induced immortalization of primary T cells, and the constitutive NF-κB activation and survival of HTLV-1 transformed T cells. IL-9 was identified as an important downstream target gene of the IL-17RB pathway that drives the proliferation of HTLV-1 transformed cells. Furthermore, IL-17RB was overexpressed in leukemic cells from a subset of ATL patients and also regulated NF-κB activation in some, but not all, Tax-negative ATL cell lines. Together, our results support a model whereby Tax instigates an IL-17RB-NF-κB feed-forward autocrine loop that is obligatory for HTLV-1 leukemogenesis.