The maintenance of cellular homeostasis depends on an exquisite balance between the biosynthesis and degradation (catabolism) of macromolecules. This balance is controlled by finely tuned mechanisms triggered by environmental signals. In eukaryotic cells, two main systems are responsible for protein degradation. The first system is the ubiquitin-proteasome system that allows for the degradation of proteins with a short half-life (generally less than 5 hours). Conversely, the second system, which is strictly dependent on the lysosome and represents approximately 99% of cellular proteins, is involved in the degradation of proteins with a half-life of up to 5 hours [1
]. The latter system includes the targeting of proteins to the lysosomes and the further degradation of these proteins by lysosomal hydrolases. The major process for the delivery of proteins to the lysosome is orchestrated by a specific and highly conserved mechanism called autophagy or macro-autophagy [2
Macro-autophagy, hereafter referred to simply as autophagy, is currently the most well studied of these degradation pathways, which is likely due to its important and paradoxical role in the control of cell death and survival. Active at the basal level in the resting cell, autophagy is induced under conditions of stress and thus behaves as an adaptative survival mechanism, more particularly through amino acid recycling following the degradation of damaged organelles and macromolecules. In mammal cells, autophagy is a multistep process, including an initiation step, a nucleation step, an elongation step and, finally, a maturation step (). The initiation and nucleation steps both converge to isolate de novo
a portion of the intracellular membrane called a phagophore. The phagophore then invaginates, and its ends can fuse to generate a double-membraned vesicle referred to as the autophagosome. The autophagosome structure is delimited by several lipidic layers that sequester the cytoplasmic content and/or organelles [2
]. The strict origin of the autophagosome is still unknown, but it is thought that several cellular compartments, including the endoplasmic reticulum (ER), the Golgi/trans-Golgi apparatus and the plasma membrane, can participate in the genesis of the autophagosome. Finally, following an additional maturation step, the autophagosome becomes an amphisome after it fuses with multivesicular endosomes (). During this step, the amphisome is acidified via the activation of proton pumps contributed by the endosomes. Ultimately, this amphisome will fuse with a lysosome to become an autolysosome in which the internal content is degraded by lysosomal enzymes ().
Figure 1 Schematic view of the autophagic process and its components. Macro-autophagy, or autophagy, is a multistep process including an initiation step, a nucleation step, an elongation step and, finally, a maturation step. In response to nutrient deprivation, (more ...)
From yeast to mammals, all of the processes of autophagosome biogenesis are controlled by the specific interaction of several protein complexes composed of Atg proteins (autophagy-related genes). Of a total of 30 Atg proteins identified to date, approximately 50% play an essential role in the formation and elongation of the phagophore. With the exception of Atg9, none of these proteins possesses a transmembrane domain. Once recruited into the cytoplasm, Atg proteins bind transiently to the membranes of the phagophore (or the pre-autophagosomal structure, PAS in yeast) and the autophagosome [3
The Atg proteins can be classified into three functional groups according to the autophagy step in which they participate (): 1) The complex composed of the serine/threonine kinase ULK1 (or its yeast homolog Atg1), mAtg13, FIP200 and Atg101 are involved in the initiation step of the phagophore. 2) The Atg6/Beclin 1-Atg14/Atg14L-Vps34-Vps15 and Beclin 1-UVRAG-Vps34-Vps-15 complexes are required for phagophore nucleation. 3) The two conjugation systems composed of Atg5-Atg12 and Atg8/LC3-PE are essential for the elongation and closure of the autophagosome [2
]. Notably, the mAtg9/Atg9 complex is important during the induction of autophagy, although its exact role in the autophagic process remains unknown. Atg9 does not belong to any of the abovementioned functional groups, but it appears to be important during all steps of autophagosome biogenesis [4
In contrast to what was initially thought, macroautophagy is not only a non-selective mechanism for the degradation of cellular constituents, but it is also now widely known that this form of autophagy is involved in the specific targeting of organelles within the cell. This targeting is called mitophagy in the case of mitochondria, pexophagy for peroxisomes and ER-phagy for the endoplasmic reticulum. Finally, the mechanism of autophagy responsible for the degradation of unfolded or aggregated proteins is referred to as aggrephagy [5
The selectivity of autophagy results in alternative molecular mechanisms that connect with and engage the autophagic machinery to use this machinery to digest specific substrates. This process requires key scaffold proteins, which have only been partially identified, that may be associated with several autophagic components to influence the selective degradation of some substrates. Importantly, several recent studies have highlighted the role of two of these adaptor proteins, p62 and NBR1, whose function is to specifically address ubiquitinated and sometimes aggregated protein substrates for autophagic degradation [6
]. Both of these proteins exhibit a high level of homology, and, although the role of NRB1 is better understood than that of p62, both proteins appear to share common functions. The present review will first focus on the structure/function relationship of p62 and then describe how p62 is regulated via several oncogenic or tumor-suppressor signaling pathways.
As a molecular adaptor between the autophagic machinery and its substrates, p62 is degraded during this autophagic process. This property led some authors to use this protein as an index for the autophagic flux measurement. We will discuss more deeply the ambiguity that occurs when using this protein as a hallmark of autophagic flux.
Finally, we will broaden our investigation into the role of autophagy in tumor development, and we will assess the impact of p62 as a molecular link between autophagy and cancer.