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The fibroblast growth factor-inducible 14 (Fn14) belongs to the TNF receptor superfamily. Fn14 is a unique receptor being highly inducible, mainly in response to tissue injury and solid tumor formation. The only ligand it is known to bind is the TNF-like weak inducer of apoptosis (TWEAK), which activates the NF-kB signaling pathway. Fn14 is constitutively synthesized and cycle between the Golgi and the plasma membrane, internalized and dispatched for lysosomal degradation independently on ligand binding. In the present study we tested the relationship between autophagy, a major stress-activated cellular pathway, and Fn14 subcellular localization. Our data shows that deletion of several key autophagic factors leads to an increase in Fn14 levels. Importantly, we found that members of the mammalian ATG8s protein family regulate different stages of Fn14 trafficking: GABARAP or LC3C regulate Fn14 autophagic turnover while GATE-16 or LC3B regulate Fn14 trafficking within the endolysosomal system.
Taken together our results provide a new link between the autophagic machinery and the trafficking and function of a TNF receptor family member.