Membrane targeting of core autophagy players during autophagosome biogenesis.

Leo J Dudley,Noor Gammoh,Agata N Makar

doi:10.1111/febs.15334

Abstract

Autophagosomes are vital organelles required to facilitate the lysosomal degradation of cytoplasmic cargo, thereby playing an important role in maintaining cellular homeostasis. A number of autophagy-related (ATG) protein complexes are recruited to the site of autophagosome biogenesis where they act to facilitate membrane growth and maturation. Regulated recruitment of ATG complexes to autophagosomal membranes is essential for their autophagic activities and is required to ensure the efficient engulfment of cargo destined for lysosomal degradation. In this review, we discuss our current understanding of the spatiotemporal hierarchy between ATG proteins, examining the mechanisms underlying their recruitment to membranes. A particular focus is placed on the relevance of phosphatidylinositol 3-phosphate and the extent to which the core autophagy players are reliant on this lipid for their localisation to autophagic membranes. In addition, open questions and potential future research directions regarding the membrane recruitment and displacement of ATG proteins are discussed here.

Highlights

The engulfment of cellular cargo by autophagosomes and the eventual recruitment of lysosomes are essential steps in the clearance of unwanted material during autophagy [1]
The unc-51-like kinase (ULK) complex is subjected to post-translational modifications by upstream signalling complexes to regulate the initiation of autophagy and the vacuolar protein-sorting 34 (VPS34) complex can modify the composition of membranes
Large deletions in the coiled-coil domains (CCDs) of ATG14 abrogated its interaction with VPS34 and Beclin 1 but did not affect its punctate localisation, suggesting that components of the VPS34 complex I are dispensable for the recruitment of ATG14 to the phagophore [35]. This CCD deletion mutant of ATG14 was still able to colocalise with the downstream autophagy player, ATG16L1, despite the lack of VPS34 binding and, presumably, VPS34 activity at these autophagic structures. These findings suggest that other lipids or lipid kinases and/or phosphatases may play a role in compensating for the loss of VPS34mediated PI(3)P biogenesis at the phagophore [14]

Summary

Introduction

The engulfment of cellular cargo by autophagosomes and the eventual recruitment of lysosomes are essential steps in the clearance of unwanted material during autophagy [1]. Whilst the initial localisation of the ULK complex to the phagophore is thought to occur independently of VPS34 activity [19], PI(3)P was shown to stabilise it on the phagophore by directly interacting with ATG13 [13]. The loss of ULK1 recruitment to the phagophore in the absence of ATG13 or FIP200 binding could be a result of its inhibited kinase activity, which requires the assembly of the ULK complex [20,27].

Results

Conclusion