Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 240

( Høyer-Hansen et al., 2007 ). CaMKKβ is activated by ER stress-induced
calcium release, and in turn activates AMPK, leading to the inhibition of
mTOR and induction of autophagy ( Høyer-Hansen et al., 2007 ; Høyer-
Hansen and Jäättelä, 2007 ).
4.2.3. Examples of ER Proteins Degraded by ERAD and/or Autophagy
Supporting the notion that autophagy is as important as ERAD for deg-
radation of terminally misfolded ER proteins, recent studies have shown
that dual degradation mechanisms exist for certain proteins, such as α1-
antitrypsin and mutant fibrinogen. Both mutant proteins form aggregates
in the ER, which, if not cleared, promote cell death. Recent studies have
shown that high levels of α1-antitrypsin or mutant fibrinogen can satu-
rate the ERAD pathway, leading to the accumulation of protein aggregates
that must be cleared through the autophagy pathway ( Kruse et al., 2006a ,
2006b ). Another example where dual degradation pathways are observed is
dysferlin. While wild-type dysferlin is degraded through the ERAD path-
way, mutant dysferlin forms protein aggregates that impair ERAD and are
degraded through autophagy ( Fujita et al., 2007 ). ERAD and autophagy
also play a role in serpin and procollagen degradation. ERAD seems to
have a selective role in mutant neuroserpin degradation, while autophagy
degrades all forms of neuroserpins. Thus, autophagy becomes an important
clinical target since induction of this degradation pathway could help to
overcome the accumulation of mutant protein aggregates ( Kroeger et al.,
2009 ). Autophagy degrades misfolded procollagen that accumulates as tri-
mers, while the misfolded procollagen monomers are degraded through the
ERAD pathway ( Ishida and Nagata, 2009 ; Ishida et al., 2009 ). Interestingly,
EDEM1, a protein involved in quality control and ERAD, is also degraded
through autophagy, suggesting that the ERAD pathway may be regulated
by autophagy ( Le Fourn et al., 2009 ).
4.3. ER-phagy
ER-phagy, as well as mitophagy and peroxiphagy, are organelle-specific
autophagic processes that degrade ER, mitochondria or peroxisomes,
respectively. ER-phagy is a specific process, which uses several autophagy
genes induced by ER stress. Normally, ER stress increases the volume of
the ER in order to inhibit protein-protein aggregation. ER-phagy is the
sequestration of ER into double-membrane vesicles. Interestingly, both the
sequestered content and the vesicle-forming membranes are of ER ori-
gin, which suggests that the ER engulfs itself in order for ER-phagy to