When including mammalian target of rapamycin complex 1

When the autophagosome completes closing of the elongating ends ofthe phagophore membrane, the subsequent step towards maturation in this processis fusion of the autophagosome with the specialized endosomal component whichis the lysosome to form the autolysosome (Parzych and Klionsky, 2014).      It has been suggestedthat fusion of the autophagosome with early and late endosomes, before fusionwith the lysosome, both delivers cargo and components of the membrane fusionmachinery and decreases the pH of the autophagic vesicle before delivery oflysosomal acid proteases (Eskelinen, 2005). Inside the lysosome, destructionof the inner vesicle is relied on a set of lysosomal acid hydrolases, includingcathepsin B, D and L and proteinases A and B in mammalian cells.The formed small molecules, particularly amino acids, are translocated back tothe cytosol for protein synthesis and maintenance of cellular functions understarvation circumstances (Tanida et al.

, 2005).  Signalling Pathways RegulatingAutophagy:     Autophagy is active atbasal levels in most cell types where it is suggested to play a housekeepingrole in maintenance of the integrity of intracellular proteins and organelles.However, autophagy is highly stimulated by various events such as starvation, oxidative stress and inflammation.It is a key tool of the adaptive response of cells and organisms to nutrient privationwhich induces survival until nutrients become available again (Weikel etal., 2014).          Regulation ofstarvation-induced autophagy includes complex signaling pathways which are controlledby the activities of multiple kinases including mammalian target of rapamycincomplex 1 (mTORC1), AMP-activated protein kinase (AMPK), and uncoordinated-51-likekinase 1 (ULK1) (Wirth et al., 2013). Under low nutrient events, thesekinases (among others) coordinate the formation of an autophagosome (Figure 1.

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15).       Under low nutrientconditions, AMPK is stimulated and directly phosphorylates the raptorcomponent of mTORC1 facilitating its dissociation from the ULK1 complex. Thus drivesULK1 to be active.

AMPK can also directly activate ULK1 by phosphorylationcausing it to translocate to the site of autophagosome membrane biogenesis. Asthe autophagosomal membrane elongates, LC3-II binds to the inner membrane ofthe forming autophagosome and acting as a receptor that connects with adaptormolecules on the target to induce their degradation by proteases (Weikel etal., 2014).      Under nutrient excessconditions, mTORC1 kinase isactivated downstream of Akt kinase, PI3-kinase and growth factor receptor signalling(Sabatini, 2006). Activation of TOR by nutrients and growth factors resultsin inhibition of autophagy through the phosphorylation of multipleautophagy-related proteins, such as Atg13, which promote autophagy initiation (Kimand Guan, 2015).

Figure (1.15) Simplified model of starvation-induced autophagy (Weikel etal., 2014).      So, TOR kinase is suppressedby signals which sense nutrient deprivation, including hypoxia, and can beartificially inhibited by treatment of cells with rapamycin (Sabatini,2006).

 

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