br Conflict of interest br Acknowledgments This work

Conflict of interest
Acknowledgments This work was been partially supported by the following grants: C.I.S.I.A. project (Innovazione e Sviluppo del Mezzogiorno—Conoscenze Integrate per Sostenibilità ed Innovazione del Made in Italy Agroalimentare—Legge 191/2009) from the Italian Ministry of Economy and Finance and the Italian National Research Council; BenTeN project (Wellness from biotechnologies: New Processes and Products for Nutraceutical, Cosmeceutical and Human Nutrition), within the Biotechnology Network of Campania Region (Italy); CAMPUS-QUARC project, FESR Campania Region programme 2007/2013, objectives 2.1, 2.2.
Introduction Autophagy had been referred to as “self-eating”, catabolic processes through which N6-Methyl-ATP degrade its own components. Recently a bulk of evidences suggested that autophagy has a broad biogenesis function in the trafficking and secretion of proteins. Interestingly, autophagy controls substitutional trafficking pathways for entire membrane proteins to the plasma membrane, which involves regulated constitutive and unconventional secretion pathways. Autophagy relies on Atg (autophagy) factors and on double-membrane vesicles in the cytoplasm called autophagosomes. Although there are confluence evidences on the origin of autophagy, studies suggested that plasma membrane, Golgi and endosomal system also contribute to the biogenesis of autophagosomes membrane [1,2]. The processes of autophagic flux and autophagosomal formation are under the control of several systems [3]. The first system represents the proteins which participate in conjugation systems: Atg7-Atg3-Atg8 and Atg5-Atg12/Atg16L. In this system phosphatidylethanolamine (PE) binds to Atg8 resulting in Atg8-PE, also known as LC3-II, a marker of mammalian autophagosomes. The second system is centered on the Ser/Thr kinase Atg1 (mammalian UNC51- like kinase 1/2 (ULK1/2), which is controlled by AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) [4]. AMPK and mTOR regulate autophagy during starvation and fed conditions. The third system is based on Atg6 (Beclin1), which interferes with different proteins such as Class III PI3K, Vps34 [5]. Autophagy assists the movement of integral membrane proteins to the cell membrane by supporting alternative trafficking pathways such as regulated, constitutive and unconventional secretion pathways. However, the conventional autophagy pathway involves ER-to-Golgi secretory pathway leading to extracellular export, while unconventional secretion depends on trafficking of whole membrane proteins to the cell membrane or delivering of different cytosolic proteins to the extracellular environment without passing via the Golgi route to their final destination [3,6]. Autophagy-based unconventional secretion (autosecretion) plays a role in protein trafficking and secretion. Example of proteins which secreted by unconventional pathway are, interleukin (IL) IL-18, IL-1b, and high mobility group protein B1 (HMGB1) in mammals. Atg factors modulate the secretion of these leaderless proteins while Golgi reassembly and stacking protein (GRASP) participates in the secretion of the proteins. Interestingly, a recent study showed that cystic fibrosis transmembrane conductance regulator (CFTR) protein utilise GRASP55, ATG7 and ATG5 as well as unconventional transport to reach the plasma membrane (CFTR bypassing ER-Golgi pathway) [3,7]. Another protein which is controlled by autophagy is glucose transporter 1 (GLUT1). Autophagy has been proved to play an important role in glucose uptake via enhancing cell surface expression of the glucose transporter GLUT1. In 2017, a study revealed that LC3+ compartments prevent the inhibitory effect of Tre-2/Bub2/Cdc16 (TBC)-1D5 on remoter complex, therefore allowing retromer recruitment to endosome membranes and GLUT1 plasma membrane translocation [8]. Collectively, it is clear that autophagy regulates the trafficking and secretion of various proteins.