Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 237

cycles of glucosylation ( Hebert et al., 2005 ). Other lectins like EDEM work
as acceptors for terminally misfolded proteins accelerating the demanno-
sylation process ( Olivari et al., 2006 ). Overexpression of EDEM greatly
accelerates protein degradation while its downregulation prolongs folding
attempts and delays protein degradation ( Molinari et al., 2003 ). Altogether,
the ER quality-control system ensures that correctly folded proteins
leave the ER while incorrectly or terminally misfolded proteins are retained
in the ER and degraded.
4.2. Misfolded Protein Degradation through ERAD and
Autophagy
Terminally misfolded proteins can be degraded through two different
pathways: The ubiquitin-proteasome pathway named ERAD and the lyso-
somal pathway termed macroautophagy (hereafter referred to as autophagy).
The ERAD pathway consists in the retrotranslocation, polyubiquitina-
tion and proteasomal degradation of misfolded proteins from the ER
( Meusser et al., 2005 ). Terminally misfolded proteins are translocated across
the ER membrane into the cytoplasm where they are covalently bound
to ubiquitin through a lysine residue. Attachment of multiple ubiquitins
yields polyubiquitin chains, which are a signal for degradation inside a
cylinder-shaped protein complex, termed the proteasome . Once inside the
proteasome, the protein becomes a substrate for the multiple proteolytic
activities present, which degrade the target protein and recycle the polyu-
biquitin side chain ( Vembar and Brodsky, 2008 ). On the other hand, during
autophagy, different molecular components such as proteins, lipids or even
entire organelles are sequestered into double-membrane vesicles, which
then fuse with lysosomes, to allow the degradation of vesicle contents ( He
and Klionsky, 2009 ).
Although ERAD has been described as the primary source for ER
misfolded protein degradation, recent reports have shown that autophagy
is involved in the removal of certain ER proteins such as α1-antitrypsin.
These observations identified autophagy as an alternative cellular strategy to
eliminate unfolded proteins ( Yorimitsu et al., 2006 ; Yorimitsu and Klionsky,
2007 ).
4.2.1. ERAD
The exact mechanism by which ERAD substrates are retrotranslocated
across the ER membrane is still a matter of debate. Several proteins have
been identified that play an essential role in this process by creating a channel