Abstract
Despite recently uncovered connections between autophagy and the endocytic pathway, the role of autophagy in regulating endosomal function remains incompletely understood. Here, we find that the ablation of autophagy‐essential players disrupts EGF‐induced endocytic trafficking of EGFR. Cells lacking ATG7 or ATG16L1 exhibit increased levels of phosphatidylinositol‐3‐phosphate (PI(3)P), a key determinant of early endosome maturation. Increased PI(3)P levels are associated with an accumulation of EEA1‐positive endosomes where EGFR trafficking is stalled. Aberrant early endosomes are recognised by the autophagy machinery in a TBK1‐ and Gal8‐dependent manner and are delivered to LAMP2‐positive lysosomes. Preventing this homeostatic regulation of early endosomes by autophagy reduces EGFR recycling to the plasma membrane and compromises downstream signalling and cell survival. Our findings uncover a novel role for the autophagy machinery in maintaining early endosome function and growth factor sensing.
Highlights
Vesicular trafficking processes are important in controlling various aspects of cell fate decisions and homeostasis
The results presented here outline a novel role for autophagy in regulating early endosome homeostasis
Ligand binding stimulates the activation of receptor tyrosine kinases (RTKs) leading to their internalisation via clathrin-dependent or clathrin-independent means [63]
Summary
Vesicular trafficking processes are important in controlling various aspects of cell fate decisions and homeostasis. Endocytosis begins with the internalisation of plasma membrane cargoes into early, or “sorting”, endosomes marked by specific adaptor proteins and small Rab GTPases [1,2,3] These vesicles can mature into endosomes destined for various cellular compartments including the plasma membrane (recycling endosomes) or lysosomes (late endosomes), thereby regulating the activities of endocytic cargoes such as receptor tyrosine kinases (RTKs) [4]. Efficient signalling from a subset of endocytosed RTKs has been shown to utilise autophagy-related membranes as signalling platforms [5,6,7], suggesting that autophagy proteins can regulate pro-growth signalling independent of their degradative function This is of particular interest given that the perturbed activities of many RTKs, including the epidermal growth factor receptor (EGFR), have been associated with various cancers and developmental defects [8,9,10,11]
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