Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling

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.

Membrane Heterogeneity Controls Cellular Endocytic Trafficking

“…EGFR is recycled to the plasma membrane or degraded in the lysosome dependent on the concentration of EGF present. At low to medium EGF concentrations, EGFR is internalized by clathrin-dependent endocytosis into multiple potential endosomal subpopulations: AAPL + endosomes for continued signaling and subsequent recycling, autophagosomes for recycling and EEA1 + endosomes for degradation (Leonard et al, 2008;Flores-Rodriguez et al, 2015;Fraser et al, 2019;Lakoduk et al, 2019). At high EGF concentrations or inhibition of clathrin, EGF is taken up independently of clathrin via macropinocytosis and delivered to the lysosome for degradation, ensuring signaling is terminated (Ménard et al, 2018).…”

The impact of autophagy during the development and survival of glioblastoma

“…Accumulating evidence suggest an interaction between RTK signalling and autophagy [ 116 ]. Autophagy players can facilitate RTK signalling thereby potentially supporting the development of glioblastoma tumours that rely on RTK activation [ 106 , 117 , 118 ]. On the other hand, RTK signalling can suppress autophagy [ 66 ] and their chemical inhibition is widely known to activate autophagy in cells [ 116 ].…”

“…Autophagy can regulate RTK signalling through various mechanisms. The loss of autophagy in immortalized glial cells has been shown to disrupt endosomal homeostasis, consequently perturbing EGFR trafficking and signalling in response to growth factor stimulation thereby reducing cell survival [ 117 ]. This was bypassed by EGFRvIII overexpression [ 117 ], with the difference in autophagy dependency likely to reflect its altered intracellular trafficking compared to wild-type EGFR [ 119 ].…”

Rab GTPases in Osteoclastic Bone Resorption and Autophagy

“…Membrane trafficking includes processes involved in the movement of various macromolecular cargoes via membrane-bound transport vesicles and can be divided into the secretory and endocytic pathways [ 2 ]. While macroautophagy (hereinafter called autophagy) relies on secretory and endocytic pathways for the directed recycling or degradation of cargoes [ 3 , 4 ], transcytosis in polarized cells involves the transport of cargo from one side of the cell to the other or redistribution of the plasma membrane [ 5 ]. As small Rab guanosine triphosphate hydrolases (GTPases) are essential for the regulation of the vesicular traffic [ 6 ], they play a major role in osteoclasts.…”