Autophagy differentially regulates TNF receptor Fn14 by distinct mammalian Atg8 proteins

• Published in: Nature communications Vol. 9; no. 1; pp. 3744 - 11
• Main Authors: Winer, Hila, Fraiberg, Milana, Abada, Adi, Dadosh, Tali, Tamim-Yecheskel, Bat-Chen, Elazar, Zvulun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-09-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/89; 13/95; 14/1; 14/19; 631/80/313/1624; 631/80/39/2346; 82/29; Adaptor Proteins, Signal Transducing - metabolism; Autophagy; Autophagy - genetics; Autophagy-Related Protein 8 Family - metabolism; Cell Line, Tumor; Cytokine TWEAK - metabolism; Endoplasmic Reticulum - metabolism; Endosomes; GABARAP protein; Gene Expression Regulation; Golgi Apparatus - metabolism; HeLa Cells; Humanities and Social Sciences; Humans; Intracellular signalling; Lysosomes; Membrane trafficking; Membranes; Microtubule-Associated Proteins - metabolism; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Phagocytosis; Phagosomes; Proteins; Science; Science (multidisciplinary); Signal Transduction; Signaling; Tumor necrosis factor; Tumor necrosis factor receptors; Tumorigenesis; TWEAK protein; TWEAK Receptor - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06275-1

Autophagy, a conserved membrane trafficking process, sequesters cytoplasmic components into autophagosomes and targets them for lysosomal degradation. The TNF receptor Fn14 participates in multiple intracellular signaling pathways and is strongly induced upon tissue injury and solid tumorigenesis. While Fn14 is a short-lived protein, the regulation of its levels is largely obscure. Here we uncover a role for autophagy in Fn14 turnover, wherein specific core autophagy Atg8 proteins play distinct roles: Fn14 accumulates in the ERGIC in absence of GABARAP but within endosomes in the vicinity of autophagic membranes in absence of GATE-16. Moreover, GABARAP regulates overall cellular levels of Fn14, whereas GATE-16 regulates TWEAK signaling by Fn14 and thereby NF-κB activity. These findings not only implicate different Atg8 proteins in distinct roles within the mechanism of selective autophagic regulation of Fn14, but may also provide a more general view of their role in mediating autophagosome biogenesis from different membrane sources.
The TNF receptor Fn14 is a short-lived protein. Here the authors show that Fn14 turnover is regulated by selective autophagy, with different ATG8 proteins having distinct roles during the process.