Elsevier

Biochimie

Volume 90, Issue 2, February 2008, Pages 313-323
Biochimie

Research paper
Regulation of macroautophagy by mTOR and Beclin 1 complexes

https://doi.org/10.1016/j.biochi.2007.08.014Get rights and content

Abstract

Macroautophagy or autophagy is a vacuolar degradative pathway terminating in the lysosomal compartment after forming a cytoplasmic vacuole or autophagosome that engulfs macromolecules and organelles. The original discovery that ATG (AuTophaGy related) genes in yeast are involved in the formation of autophagosomes has greatly increased our knowledge of the molecular basis of autophagy, and its role in cell function that extends far beyond non-selective degradation. The regulation of autophagy by signaling pathways overlaps the control of cell growth, proliferation, cell survival and death. The evolutionarily conserved TOR (Target of Rapamycin) kinase complex 1 plays an important role upstream of the Atg1 complex in the control of autophagy by growth factors, nutrients, calcium signaling and in response to stress situations, including hypoxia, oxidative stress and low energy. The Beclin 1 (Atg6) complex, which is involved in the initial step of autophagosome formation, is directly targeted by signaling pathways. Taken together, these data suggest that multiple signaling checkpoints are involved in regulating autophagosome formation.

Introduction

Cell homeostasis depends on the balance between the biosynthesis and catabolism of macromolecules. There are two major systems in eukaryotic cells that degrade cellular components: the proteasome and the lysosome [1]. The proteasomal degradative pathway is selective for proteins. The lysosomal system is responsible for the degradation of several classes of macromolecules, and for the turnover of organelles by several mechanisms collectively known as autophagy. This term embraces several different mechanisms: microautophagy, macroautophagy, crinophagy and chaperone-mediated autophagy [2]. This review will focus, except where otherwise indicated, on macroautophagy (hereafter referred to as autophagy), a process that degrades macromolecules, and also eliminates organelles and unwanted structures. Autophagy is a mechanism conserved among eukaryotic cells that starts with the formation of a double membrane-bound vacuole, known as an autophagosome, which ultimately fuses with the lysosomal compartment to degrade the sequestered material. The discovery of ATG genes in the yeast Saccharomyces cerevisiae that govern autophagosome formation has boosted research on autophagy in the last decade [3], [4], [5]. Most of these genes are conserved from yeast to human and several reviews have been dedicated to the role of Atg proteins in the different steps of the formation of autophagosomes [3], [6], [7]. Autophagy occurs at a basal rate in most cells, where it acts as a cytoplasmic quality control mechanism to eliminate protein aggregates and damaged organelles [8]. The physiological importance of basal autophagy in maintaining tissue homeostasis has been recently demonstrated in conditional brain and liver ATG knockout mouse models [9], [10], [11]. These studies have also demonstrated the role of autophagy in preventing the deposition of aggregate-prone proteins in the cytoplasm, and the non-selective contribution of autophagy to the elimination of ubiquitinated proteins that are efficient substrates for the proteasome [12], [13], [14]. The anti-aging role of autophagy probably depends, at least in part, on its quality control function that limits the deposition of aggregate-prone proteins and the formation of damaging reactive oxygen species by mitochondria [15]. On the other hand, when the supply of nutrients is limited, stimulating autophagy contributes to the lysosomal recycling of nutrients to maintain protein synthesis and glucose synthesis from amino acids (in the liver), and substrates for oxidation and ATP production in the mitochondria [8], [16] and inhibition of the default apoptotic pathway [17]. In vivo, a recent study showed that at birth the sudden interruption of the supply of nutrients via the placenta triggers autophagy in newborn mouse tissues to maintain energy homeostasis and survival [18].

Autophagy has also been recently recognized as a mechanism contributing to the innate immune response toward pathogens [19], [20], [21], [22], [23], [24], and to antigen presentation by MHC class II [25], [26], [27]. It is also implicated in numerous diseases, including, cancer, neurodegenerative disease, muscle and liver disorders. Several reviews have discussed the beneficial or harmful role of autophagy in these diseases [28], [29], [30], [31], [32], [33], [34].

Although autophagy is recognized as being a cytoprotective process, for some years it has also been suspected of being involved in type-2 Programmed Cell Death (PCD) or autophagic cell death (as distinct from type-1 PCD or apoptosis) (reviewed in [35]). Only recently, genetic studies have shown that cells can be killed by autophagy when apoptosis is inhibited [36], [37], [38]. Moreover, in a different context it has been shown that autophagy contributes with apoptotic signals to the killing of cells [39], [40], [41], [42], [43] and elimination of apoptotic cells by phagocytic cells [44].

It is now important to elucidate the regulation of autophagy in order to clarify its dual effects in cell survival and cell death. The knowledge of the relationship between signaling pathways and the molecular machinery involved in the formation of autophagosomes will be essential. Recent studies suggest that the regulation of autophagy overlaps with that of apoptosis, and that signaling molecules may modulate several different players in the autophagic molecular machinery [43], [45]. The aim of the present review is to describe the roles of two major protein complexes (mTOR complex 1 and the Beclin 1 complex) in the regulation of autophagy and their consequences for the outcome of autophagy.

Section snippets

The morphology of autophagy and the autophagic machinery: an overview

The aim of this section is to briefly summarize what we know about the anatomy of autophagy, and the role of Atg and other proteins involved in the formation and maturation of autophagosomes. For more detailed discussions, readers should consult recent reviews dedicated to the morphology of autophagy [46], [47], the origin of the membrane source for autophagy [48], [49], [50], the role of Atg proteins during the formation of autophagosomes [6], [7] and the molecular events that govern the

mTOR complexes

TOR is a conserved Ser/Thr protein kinase that regulates cell growth, cell cycle progression, nutrient import, protein synthesis and autophagy [62], [63], [64], [65], [66]. The discovery of this kinase is rooted in a soil sample from Easter Island containing a bacterium (Streptomyces hygroscopicus) that produces the antifungal metabolite, rapamycin (from “Rapa Nui”, the local name for Easter Island). Rapamycin binds to the FKBP12 protein to form a complex that interacts and inhibits several

Beclin 1 complex

Beclin 1 was originally discovered from a mouse brain library using a yeast two-system hybrid with the antiapoptotic protein Bcl-2 as bait [117]. It is a 60-kDa protein containing 450 amino acids that comprise four specific domains: (1) a Bcl-2 binding domain extending from amino acids 88 to 150; (2) a coil-coiled domain from amino acids 150 to 244; (3) an evolutionarily-conserved domain from amino acids 244 to 337; and (4) a nuclear export signal from amino acids 180 to 190. This last domain

Concluding remarks

The signaling of autophagy depends on two tightly regulated complexes. mTORC1 signaling inhibits autophagy, and is also able to regulate other processes such as protein translation. In contrast, the only known function of the Beclin 1 complex is to stimulate autophagy. However, in yeast, the Atg6/Vps30 complex controls both autophagy and the trafficking of lysosomal enzymes. One important aspect of extending our knowledge of how Beclin 1 regulates autophagy will involve identifying the

Acknowledgements

Work in P. Codogno's laboratory is supported by institutional funding from The Institut National de la Santé et de la Recherche Médicale (INSERM) and grants from the Association pour la Recherche sur le Cancer to SP and PC. This work was also supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), Montpellier I and II Universities and grants from SIDACTION and the Agence Nationale de Recherches sur le SIDA (ANRS). LE was the recipient of a fellowship from

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