Regulation of Fibroblast Growth Factor-inducible 14 ( Fn14) Expression Levels via Ligand-independent Lysosomal Degradation

Background: Fn14 is a highly inducible TNF superfamily cytokine receptor. Results: Fn14 undergoes rapid, ligand-independent internalization and degradation mediated by the extracellular domain of the receptor. Conclusion: Fn14 expression is regulated through transcription as described previously and through a novel post-translational mechanism. Significance: Receptor trafficking may play an important role in regulating receptor availability, cytokine responses, and ligand-independent signaling. Fibroblast growth factor-inducible 14 (Fn14) is a highly inducible cytokine receptor that engages multiple intracellular signaling pathways, including nuclear factor-B (NF-B) and mitogen-activated protein kinase (MAPK). Fn14 expression is regulated by several cytokines and growth factors, and Fn14 is transiently up-regulated after injury. In contrast, in states of chronic inflammatory disease and in some solid tumors, Fn14 is persistently up-regulated. However, the post-translational regulation of Fn14 expression has not been directly investigated. Thus, we examined Fn14 proteostasis in the presence and absence of the Fn14 ligand TNF-like weak inducer of apoptosis (TWEAK). Similar to other TNF receptor superfamily members, we found that TWEAK induces Fn14 internalization and degradation. Surprisingly, we also observed rapid, TWEAK-independent, constitutive Fn14 internalization and turnover. Fn14 levels are maintained in cell culture by ongoing synthesis and trafficking of the receptor, leading to subsequent down-regulation by lysosomal degradation. Unexpectedly, the extracellular domain of Fn14 is necessary and sufficient for constitutive turnover. Based on these findings, we propose a model in which constitutive down-regulation of Fn14 facilitates dynamic regulation of Fn14 protein levels and prevents spontaneous or inappropriate receptor signaling.