Autophagy: New Questions from Recent Answers

Abstract

Macroautophagy (hereafter autophagy) is currently one of the areas of medical life sciences attracting a great interest because of its pathological implications and therapy potentials. The discovery of the autophagy-related genes (ATGs) has been the key event in this research field because their study has led to the acquisition of new knowledge about the mechanism of this transport pathway. In addition, the investigation of these genes in numerous model systems has revealed the central role that autophagy plays in maintaining the cell homeostasis. This process carries out numerous physiological functions, some of which were unpredicted and thus surprising. Here, we will review some of the questions about the mechanism and function of autophagy that still remain unanswered, and new ones that have emerged from the recent discoveries.

Figure 1

Schematic representation of the process of autophagy. Phagophores are the initial precursor structure of this transport pathway. These membrane cisterns are formed at the PAS by the Atg machinery, which also catalyzes their expansion into autophagosomes through the acquisition of extra lipid bilayers. During this latter event, the growing phagophore sequesters cytoplasmic components or specific structures depending on the autophagy-inducing conditions. The closure of the expanding phagophore leads to the formation of a double-membrane vesicle called an autophagosome, which contains the cargo targeted for degradation. The Atg machinery is then released from the surface and the complete autophagosomes, which initially fuse with endosomal compartments generating amphisomes. While the cargo material starts to be already turned over in the amphisomes, the exposure to hydrolases by fusion with lysosomes to form autolysosomes allows its complete degradation into basic metabolites such as amino acids and sugars, which are transported in the cytoplasm and used as an energy source or building blocks for the synthesis of new macromolecules. Adapted from [8, 9].

Figure 2

The organisation of the Atg machinery in functional groups. Yeast ATGs are in blue while the mammalians counterparts, which in few cases comprise few paralogues, are in red. The WIPI's is a protein family which comprises 4 members: WIPI1, WIPI2, WIPI3, and WIPI4 [20]. Three of them have been shown to be involved in autophagy [–22]. The LC3's is a protein family that comprise 6 proteins: LC3A, LC3B, LC3C, GABARAPL1, GABARAPL2, and GABARAPL3 [23]. All of them associate with autophagosomes [23, 24]. The yeast Atg1 complex contains two subunits, Atg29 and Atg31, which do not have homologues in high eukaryotes. In contrast, the mammalian complex possesses a component, Atg101, which is not found in yeast.