Phagophores evolve from recycling endosomes

Abstract

The membrane origins of autophagosomes have been a key unresolved question in the field. The earliest morphologically recognizable structure in the macroautophagy/autophagy itinerary is the double-membraned cup-shaped phagophore. Newly formed phosphatidylinositol 3-phosphate (PtdIns3P) on the membranes destined to become phagophores recruits WIPI2, which, in turn, binds ATG16L1 to define the sites of autophagosome formation. Here we review our recent study showing that membrane recruitment of WIPI2 requires coincident detection of PtdIns3P and RAB11A, a protein that marks recycling endosomes. We found that multiple core autophagy proteins are more tightly associated with the recycling endosome compartment than with endoplasmic reticulum (ER)-mitochondrial contact sites. Furthermore, biochemical isolation of the recycling endosomes confirmed that they recruit autophagy proteins. Finally, fixed and live-cell imaging data revealed that recycling endosomes engulf autophagic substrates. Indeed, the sequestration of mitochondria after mitophagy stimulation depends on early autophagy regulators. These data suggest that autophagosomes evolve from the RAB11A compartment.

Keywords: Autophagosome origin; RAB11; WIPI2; recycling endosome.

Figure 1.

The figure shows how TFRC is endocytosed together with its ligand, TF (purple dot), from the plasma membrane (PM) to recycling endosomes (RE) during starvation. The extracellular domain of this receptor is concentrated between the inner and outer evolving phagophore membranes, labeled by RAB11A and PtdIns3P. RAB11A and PtdIns3P constitute a ‘coincident-detection’ signature for WIPI2 membrane recruitment. ‘Curvature’ and ‘Scission’ are important events for the evolution of phagophores from the recycling endosome, which need further mechanistic exploration.