Moreover, AMPK can directly phosphorylate ULK1 promoting the formation of the complex ( Kim et al., 2011) that additionally requires Atg13 phosphorylation and the scaffold protein FAK family kinase interacting protein of 200 kDa (FIP200) resulting in a multi-protein complex composed of ULK1-Atg13-FIP200-ATG101. The UNC51-like kinase 1 (ULK1) kinase protein complex is responsible for the initiation step of the process and it is directly regulated by the nutrient-sensing mammalian target of rapamycin (mTOR) that, phosphorylating ULK1, prevents its interaction with the energy-sensing AMP-activated protein kinase (AMPK) and blocks the complex assembling. The proper execution of autophagy relies on the formation of two crucial protein complexes and two sequential conjugation steps. Autophagy is a multi-step process with an ordered sequence of events that include induction, nucleation of a phagophore structure, formation and maturation of autophagosome, and finally autophagosome fusion with lysosome to degrade and recycle nutrients ( Mizushima, 2007). Macroautophagy, commonly and hereafter referred to as autophagy, provides amino acids and energy from the bulk degradation and recycling of intracellular components ( Klionsky, 2007).Īt first autophagy activation was identified as the response to starvation ( Mortimore and Schworer, 1977) currently, we know that autophagy is activated in response to different cellular stressors including exercise, endoplasmic reticulum stress, infection, and hypoxia ( Kroemer et al., 2010). In microautophagy, cytoplasmic components are directly engulfed into the lysosomal compartment, while in macroautophagy, autophagosomes, characterized by a double membrane structure, surround the cytoplasmic components ( Mizushima et al., 2008) and fuse with lysosomes, where their content is degraded. In CMA, proteins with a specific motif, that are typically subjected to unfolding or denaturation, are recognized by molecular chaperones and directly driven into lysosomes. Consistently, three different pathways can be recognized: chaperone-mediated autophagy (CMA), microautophagy and macroautophagy. Systemic and tissue-specific knockout of Atg genes in murine models has proven the involvement of autophagy also in mammalian development and differentiation ( Mizushima and Levine, 2010).Īutophagy process can be distinguished according to how cargo enters the lysosome compartment. Genetic knockout of Atg genes has revealed the dependence on autophagy for the formation of spores in yeast ( Tsukada and Ohsumi, 1993) and dauer larvae in Caenorhabditis elegans ( Melendez et al., 2003), and for insect metamorphosis in Lepidoptera and Drosophila melanogaster ( Romanelli et al., 2016). Actually, autophagy is an evolutionarily conserved process, and the orthologs of most Atg genes, originally discovered in Saccharomyces cerevisiae ( Ohsumi, 2001), have been isolated and functionally characterized in higher eukaryotes. In the 1990s, the discovery of Atg genes paved the way to the awareness of the role of autophagy in embryonic differentiation and development of both invertebrates and vertebrates ( Mizushima and Levine, 2010 Agnello et al., 2015). In this review, we focus on established and recent breakthroughs aimed at elucidating the impact of autophagy in differentiation and homeostasis maintenance of endothelium, muscle, immune system, and brain providing a suitable framework of the emerging results and highlighting the pivotal role of autophagic response in tissue functions, stem cell dynamics and differentiation rates. Autophagy also controls stem cell fate and defective autophagy is involved in many pathophysiological processes. This conserved process is essential for metabolic plasticity and tissue homeostasis and is crucial for mammalian post-mitotic cells. 2Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, ItalyĪutophagy is a constitutive pathway that allows the lysosomal degradation of damaged components.1Department of Biomedical and Clinical Sciences “Luigi Sacco” (DIBIC), Università degli Studi di Milano, Milan, Italy.Cristiana Perrotta 1, Maria Grazia Cattaneo 2, Raffaella Molteni 2 and Clara De Palma 2*
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