Membrane dynamics in autophagosome biogenesis

Abstract

Bilayered phospholipid membranes are vital to the organization of the living cell. Based on fundamental principles of polarity, membranes create borders allowing defined spaces to be encapsulated. This compartmentalization is a prerequisite for the complex functional design of the eukaryotic cell, yielding localities that can differ in composition and operation. During macroautophagy, cytoplasmic components become enclosed by a growing double bilayered membrane, which upon closure creates a separate compartment, the autophagosome. The autophagosome is then primed for fusion with endosomal and lysosomal compartments, leading to degradation of the captured material. A large number of proteins have been found to be essential for autophagy, but little is known about the specific lipids that constitute the autophagic membranes and the membrane modeling events that are responsible for regulation of autophagosome shape and size. In this Commentary, we review the recent progress in our understanding of the membrane shaping and remodeling events that are required at different steps of the autophagy pathway.This article is part of a Focus on Autophagosome biogenesis. For further reading, please see related articles: 'ERES: sites for autophagosome biogenesis and maturation?' by Jana SanchezWandelmer et al. (J. Cell Sci. 128,(185)(186)(187)(188)(189)(190)(191)(192) and 'WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome' by Tassula Proikas-Cezanne et al. (J. Cell Sci. 128,(207)(208)(209)(210)(211)(212)(213)(214)(215)(216)(217).

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

“…As an additional confirmation of this result, we also monitored the formation of ATG5 and ATG12 puncta in starved cells, which is another marker for autophagosomal biogenesis. 38 , 39 , 43–45 Indeed, normal and CMT2B fibroblasts showed a similar amount of ATG5 and ATG12 puncta per cell, both in full medium and in starved cells (Fig. 6D-G), further supporting the idea that RAB7 V162M mutation does not affect autophagosomal biogenesis but acts in later steps of autophagosome maturation.…”

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

“…8 After the initiation step, a cup-shaped, primary double-membrane structure, the phagophore, is gradually formed. 8, 9 The nucleation of the phagophore membrane takes place at a site termed the phagophore assembly site (PAS) in yeast, 10 whereas an additional site, the omegasome, may play a similar role in mammalian cells. 9 The recruitment of the ULK1 and PIK3C3 complexes to the nucleation site is the initial step for autophagy, [11][12][13][14][15] and ULK1 relocalization is a prerequisite for ATG14-PIK3C3 complex targeting.…”

“…9 The recruitment of the ULK1 and PIK3C3 complexes to the nucleation site is the initial step for autophagy, [11][12][13][14][15] and ULK1 relocalization is a prerequisite for ATG14-PIK3C3 complex targeting. 11,14,15 The PIK3C3 complex generates phosphatidylinositol 3-phosphate (PtdIns3P) at the nucleation site, 16 which creates a PtdIns3P-enriched milieu, reinforcing the localization of the ULK1 complex and other ATG proteins at the growing membrane 9,12 and triggering the assembly of PtdIns3P-binding effector proteins, which is critical for the subsequent elongation of the phagophore and maturation of the autophagosome. 7,17 The ATG12 ubiquitin-like conjugation system mediates the conjugation of ATG12 to ATG5, which then binds to ATG16L1.…”

“…7,17 The ATG12 ubiquitin-like conjugation system mediates the conjugation of ATG12 to ATG5, which then binds to ATG16L1. 9,14 The latter, which resides at the elongating membrane, facilitates the subsequent modification of LC3 into a phosphatidylethanolamine (PE)-linked form. 5,9,14,15 The lipidated Figure 1.…”

“…9,14 The latter, which resides at the elongating membrane, facilitates the subsequent modification of LC3 into a phosphatidylethanolamine (PE)-linked form. 5,9,14,15 The lipidated Figure 1. Regulation of autophagy by 3 classes of PtdIns3K and PI3Ks.…”