Getting ready for building: signaling and autophagosome biogenesis

Abstract

Autophagy is the main cellular catabolic process responsible for degrading organelles and large protein aggregates. It is initiated by the formation of a unique membrane structure, the phagophore, which engulfs part of the cytoplasm and forms a double-membrane vesicle termed the autophagosome. Fusion of the outer autophagosomal membrane with the lysosome and degradation of the inner membrane contents complete the process. The extent of autophagy must be tightly regulated to avoid destruction of proteins and organelles essential for cell survival. Autophagic activity is thus regulated by external and internal cues, which initiate the formation of well-defined autophagy-related protein complexes that mediate autophagosome formation and selective cargo recruitment into these organelles. Autophagosome formation and the signaling pathways that regulate it have recently attracted substantial attention. In this review, we analyze the different signaling pathways that regulate autophagy and discuss recent progress in our understanding of autophagosome biogenesis.

Autophagy and regulation of cilia function and assembly

“…2,3,46,47,56 Regulation of autophagy: The core molecular machinery engaged in autophagosome formation, as well as the signaling pathways that stimulate autophagy have been reviewed in detail elsewhere. [57][58][59][60][61] Fifteen autophagy-related (ATG) proteins constitute the core machinery of autophagosome formation. 59 In mammalian cells, these ATG proteins are recruited to form a phagophore, or isolation membrane, which subsequently elongates to form the autophagosome (Figure 2).…”

Membrane dynamics in autophagosome biogenesis

“…It is generally agreed that phagophores are formed de novo by nucleation on a preexisting membrane (for recent reviews, see Abada and Elazar, 2014;Hamasaki et al, 2013b;Lamb et al, 2013;Shibutani and Yoshimori, 2014). In yeast, the phagophore membrane has been found to originate from a single origin near the vacuole, called the pre-autophagosomal structure (PAS) (Suzuki and Ohsumi, 2010).…”

Ambra1 at a glance

“…Under standard conditions -such as when nutrients are abundant within the cell -protein synthesis proceeds incessantly or cells might divide, and a series of cellular events regulated by the autophagy signaling network ensure quality control of cellular components and maintain cellular homeostasis. However, in the context of a vast number of stress stimuli, ranging from starvation to hypoxia or DNA damage, autophagy constitutes a key pro-survival response, thus allowing adaptation to unfavourable conditions (Abada and Elazar, 2014;Boya et al, 2013;Choi et al, 2013).…”

“…Comprehensively, the upstream autophagy signaling network includes mammalian target of rapamycin complex 1 (mTORC1), a crucial metabolic switch that normally inhibits autophagy, and the 'core autophagy machinery', mainly comprising four macromolecular complexes, which have been extensively reviewed elsewhere (see Abada and Elazar, 2014;Boya et al, 2013). Briefly, these are the unc-51-like autophagy-activating kinase 1 (ULK1) kinase complex, the class III phosphatidylinositol 3-kinase (PI3KIII) complex, the ubiquitin-like conjugation system -mainly comprising autophagy related gene 12 (ATG12) and light chain 3 (LC3) -and transmembrane proteins, such as mammalian autophagy-related gene 9 (ATG9; also known as ATG9A) (Abada and Elazar, 2014).…”

“…Briefly, these are the unc-51-like autophagy-activating kinase 1 (ULK1) kinase complex, the class III phosphatidylinositol 3-kinase (PI3KIII) complex, the ubiquitin-like conjugation system -mainly comprising autophagy related gene 12 (ATG12) and light chain 3 (LC3) -and transmembrane proteins, such as mammalian autophagy-related gene 9 (ATG9; also known as ATG9A) (Abada and Elazar, 2014).…”