TNFRSF19 inhibits TGFβ signaling through interaction with TGFβ receptor Type i to promote tumorigenesis

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFkB activation or associated with TRAF proteins. We identified TGFβ receptor type I (TbRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TbRI in the cytoplasm, thereby blocking Smad2/3 association with TbRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ. Significance: TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFβ signaling pathway.