Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 239

4.2.2. Autophagy
Autophagy is induced by nutrient deprivation. The kinase AMPK responds
to low energy levels of the cell, by sensing the declining ATP/AMP ratios.
Once activated, AMPK phosphorylates mTOR, a master regulator of
protein synthesis. mTOR normally functions as a Ser/Thr kinase, which
hyperphosphorylates Atg13, thereby impeding the activation of autophagy.
mTOR phosphorylation by AMPK reduces Atg13 phosphorylation, thus
permitting its interaction with the kinase Atg1 and activation of a phos-
phorylation cascade that leads to the recruitment and activation of a series
of Atg proteins indispensable for autophagy induction ( He and Klionsky,
2009 ; Jung et al., 2010 ). Among the most important Atgs are LC3/Atg8
and Beclin-1/Atg6. Beclin-1 is part of a protein complex termed PI3K-III,
which is important for the nucleation, recruitment and expansion of the
double membrane that eventually sequesters the substrates destined for deg-
radation. In normal conditions, Beclin-1 interacts with its inhibitor Bcl-2.
Beclin-1 dissociation from Bcl-2 is indispensable for PI3K-III function and
autophagy activation ( Kang et al., 2011 ). During the autophagic pathway,
LC3 is processed and attached to the autophagosome membrane by conju-
gation with phosphatidylethanolamine ( Klionsky et al., 2007 ).
As indicated, recent work has shown that autophagy is induced under
ER stress conditions to protect cells against death ( Ogata et al., 2006 ; Pankiv
et al., 2007 ). Work in yeast, utilizing classic ER stress inducers, such as DTT
or tunicamycin, revealed that autophagy was induced, as assessed by LC3
processing and Atg1 kinase activity ( Yorimitsu et al., 2006 ; Yorimitsu and
Klionsky, 2007 ). This correlates with other work in which Hac1, an XBP1
yeast ortholog, induced important autophagy genes such as Atg5, Atg7 and
Atg8 under ER stress conditions ( Bernales et al., 2006 ). Other studies in
mammalian cells showed that autophagy is a key component in the degra-
dation of α1-antitrypsin retained inside the ER ( Teckman and Perlmutter,
2000 ). ER-mediated regulation of autophagy has been linked to the PERK
and IRE1 pathways. PERK phosphorylation of eIF2α is involved in Atg12
upregulation and LC3 conversion during polyglutamine aggregate-induced
autophagy ( Kouroku et al., 2007 ). PERK phosphorylation of eIF2α is also
involved in the degradation of mutant dysferlin aggregates via LC3 con-
version and autophagy ( Fujita et al., 2007 ). Other studies have implicated
the IRE1 pathway in ER stress-induced autophagy. IRE1 recruits the
protein factor TRAF2, which activates JNK that phosphorylates Beclin-1,
thereby allowing dissociation from its repressor Bcl-2 ( Ogata et al., 2006 ).
ER calcium release is also thought to participate in autophagy induction