Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 238

in the ER membrane that permits retrograde transport of misfolded pro-
teins back to the cytoplasm ( Meusser et al., 2005 ). The Sec61 complex has
been proposed as a possible channel for protein retrotranslocation ( Wiertz
et al., 1996 ) although this complex was first described as a channel through
which nascent polypeptides are imported into the ER ( Mothes et al., 1994 ;
Matlack et al., 1998 ). Another possible candidate retrotranslocation channel
is Derlin-1, which forms a complex with the ubiquitin ligase Hrd-1 along
with other adaptor proteins ( Carvalho et al., 2010 ). Derlin-1 has the ability
to form structures that span the ER membrane, suggesting that this protein
may also function as a channel for ERAD retrotranslocation ( Crawshaw
et al., 2007 ).
Research in S. cerevisiae showed that protein substrates are recognized
and degraded differently, depending on whether their misfolded domain is
cytosolic (ERAD-C), transmembrane (ERAD-M) or luminal (ERAD-L)
( Carvalho et al., 2006 ). While ERAD-C substrates are rapidly degraded
through the ubiquitin ligase Doa10p ( Swanson et al., 2001 ), ERAD-L and
ERAD-M depend on the Hrd ubiquitin ligase complex for degradation
( Bordallo et al., 1998 ; Schäfer and Wolf, 2009 ). Studies in yeast using differ-
ent glycosylated and nonglycosylated degradation substrates identified the
basic components of the Hrd ubiquitin ligase complex and its adapter pro-
tein functions. The basic structure of this complex is formed by the ubiqui-
tin ligase Hrd1p, the substrate adapter protein Hrd3p, the luminal substrate
adapter proteins Der1p and Usa1p, the ubiquitin conjugating enzyme
Ubc7 and the glycan substrate adapter Yos9p ( Carvalho et al., 2006 ; Meh-
nert et al., 2010 ). Different mammalian homologs of Hrd complex proteins
have been identified by correlating with functions in yeast ( Mehnert et al.,
2010 ). Among these mammalian homologs, Herp, an ubiquitin-like ER
membrane protein, has been recently found to regulate Hrd1-dependent
ubiquitination ( Kokame et al., 2000 ; Kny et al., 2011 ). Recent studies have
shown that Herp is involved in regulating the degradation of multiple ER
substrates such as immature nicastrin and α-1 antitrypsin ( Kny et al., 2011 ;
Marutani et al., 2011 ).
Retrotranslocation across the ER membrane of misfolded, polyubiqui-
tinated proteins is an active process that requires ATP hydrolysis. The AAA-
ATPase p97 and its adapter proteins Ufd and Npl4 are necessary to generate
the driving force required for misfolded protein extraction ( Ye et al., 2001 ).
In mammalian cells, p97 binds Derlin-1 via VIMP and other cofactors,
thereby permitting recruitment of misfolded proteins to the ER membrane,
their export and proteasomal degradation in the cytoplasm ( Ye et al., 2004 ).