Abstract
Fibroblast growth factor-inducible 14 (Fn14) is a highly inducible cytokine receptor that engages multiple intracellular signaling pathways, including nuclear factor-κB (NF-κB) 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.
Highlights
factor-inducible 14 (Fn14) is a highly inducible TNF superfamily cytokine receptor
It is known that TNF-like weak inducer of apoptosis (TWEAK) binding can induce lysosomal degradation of Fn14 pathway signaling components [34], the fate of Fn14 following ligation by TWEAK is unknown
Our results suggest that steady-state Fn14 expression reflects constitutive expression and trafficking to the plasma membrane followed by rapid endocytosis and endolysosomal degradation
Summary
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. Significance: Receptor trafficking may play an important role in regulating receptor availability, cytokine responses, and ligand-independent signaling. 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. Increased Fn14 mRNA and protein levels have been detected in a number of solid tumors with elevated expression levels correlating with poor patient outcome (16 –19). Overall, it appears that Fn14 expression is induced in many chronic disease states and that persistent activation of the TWEAK-Fn14 pathway contributes to the pathology of these diseases.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
