When 2013). Under low nutrient events, these kinases

When the autophagosome completes closing of the elongating ends of
the phagophore membrane, the subsequent step towards maturation in this process
is fusion of the autophagosome with the specialized endosomal component which
is the lysosome to form the autolysosome (Parzych and Klionsky, 2014).

 

     It has been suggested
that fusion of the autophagosome with early and late endosomes, before fusion
with the lysosome, both delivers cargo and components of the membrane fusion
machinery and decreases the pH of the autophagic vesicle before delivery of
lysosomal acid proteases (Eskelinen, 2005). Inside the lysosome, destruction
of the inner vesicle is relied on a set of lysosomal acid hydrolases, including
cathepsin B, D and L and proteinases A and B in mammalian cells.
The formed small molecules, particularly amino acids, are translocated back to
the cytosol for protein synthesis and maintenance of cellular functions under
starvation circumstances (Tanida et al., 2005).

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Signalling Pathways Regulating
Autophagy:

     Autophagy is active at
basal levels in most cell types where it is suggested to play a housekeeping
role 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 privation
which induces survival until nutrients become available again (Weikel et
al., 2014).

   

     Regulation of
starvation-induced autophagy includes complex signaling pathways which are controlled
by the activities of multiple kinases including mammalian target of rapamycin
complex 1 (mTORC1), AMP-activated protein kinase (AMPK), and uncoordinated-51-like
kinase 1 (ULK1) (Wirth et al., 2013). Under low nutrient events, these
kinases (among others) coordinate the formation of an autophagosome (Figure 1.15).

 

     Under low nutrient
conditions, AMPK is stimulated and directly phosphorylates the raptor
component of mTORC1 facilitating its dissociation from the ULK1 complex. Thus drives
ULK1 to be active. AMPK can also directly activate ULK1 by phosphorylation
causing it to translocate to the site of autophagosome membrane biogenesis. As
the autophagosomal membrane elongates, LC3-II binds to the inner membrane of
the forming autophagosome and acting as a receptor that connects with adaptor
molecules on the target to induce their degradation by proteases (Weikel et
al., 2014).

 

     Under nutrient excess
conditions, mTORC1 kinase is
activated downstream of Akt kinase, PI3-kinase and growth factor receptor signalling
(Sabatini, 2006). Activation of TOR by nutrients and growth factors results
in inhibition of autophagy through the phosphorylation of multiple
autophagy-related proteins, such as Atg13, which promote autophagy initiation (Kim
and Guan, 2015).

Figure (1.15) Simplified model of starvation-induced autophagy (Weikel et
al., 2014).

 

     So, TOR kinase is suppressed
by signals which sense nutrient deprivation, including hypoxia, and can be
artificially inhibited by treatment of cells with rapamycin (Sabatini,
2006).

 

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