Autophagy differentially regulates TNF receptor Fn14 by distinct mammalian Atg8 proteins

Hila Winer,Milana Fraiberg,Tali Dadosh,Bat-Chen Tamim-Yecheskel,Zvulun Elazar,Adi Abada

doi:10.1038/s41467-018-06275-1

Hila Winer, Milana Fraiberg + Show 4 more

Open Access

https://doi.org/10.1038/s41467-018-06275-1

Copy DOI

Journal: Nature Communications	Publication Date: Sep 14, 2018
Citations: 15	License type: open-access

Affiliation: Weizmann Institute of Science

Abstract

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.

Highlights

Autophagy, a conserved membrane trafficking process, sequesters cytoplasmic components into autophagosomes and targets them for lysosomal degradation
Upon Bafilomycin A1 (BafA) treatment a discernible portion of factor inducible 14 (Fn14) localized to the Golgi apparatus and endoplasmic reticulum (ER)Golgi intermediate compartment (ERGIC), while no evidence of colocalization with the ER marker Calnexin was observed (Supplementary Fig. 1d)
We found that Fn14 vesicles formed upon depletion of Golgi-associated ATP enhancer-16 (GATE-16) are positive for the rat brain GTPase-activating protein (RabGAP) protein TBC1D5, which was recently implicated in reprogramming of endosomal trafficking to autophagosomes under autophagic conditions[49,50,51]

Summary

Introduction

A conserved membrane trafficking process, sequesters cytoplasmic components into autophagosomes and targets them for lysosomal degradation. GABARAP regulates overall cellular levels of Fn14, whereas GATE-16 regulates TWEAK signaling by Fn14 and thereby NF-κB activity These findings implicate different Atg[8] proteins in distinct roles within the mechanism of selective autophagic regulation of Fn14, but may provide a more general view of their role in mediating autophagosome biogenesis from different membrane sources. 1234567890():,; Fibroblast growth factor inducible 14 (Fn14) is a tumor necrosis factor (TNF) receptor family member that is strongly upregulated in response to tissue injury[1,2] and is overexpressed in solid tumors[3,4,5,6,7,8,9,10] It is activated by TNF-like weak inducer of apoptosis (TWEAK/TWK), a member of the TNF cytokines superfamily, that controls various cellular processes, including proliferation, migration, differentiation, apoptosis, and inflammation[1,11,12,13]. We demonstrate that autophagy plays central roles in Fn14 function and turnover through differential regulation of this receptor by distinct activities of mammalian Atg[8] proteins GABARAP and Golgi-associated ATP enhancer-16 (GATE-16)

Methods

Results

Conclusion