TY - JOUR
T1 - On the road to nowhere
T2 - Cross-talk between post-translational protein targeting and cytosolic quality control
AU - Casson, Joseph
AU - McKenna, Michael
AU - High, Stephen
PY - 2016/6/15
Y1 - 2016/6/15
N2 - A well-defined co-translational pathway couples the synthesis and translocation of nascent polypeptides into and across the membrane of the endoplasmic reticulum (ER), thereby minimizing the possibility of the hydrophobic signals and transmembrane domains that such proteins contain from being exposed to the cytosol. Nevertheless, a proportion of these co-translational substrates may fail to reach the ER, and therefore mislocalize to the cytosol where their intrinsic hydrophobicity makes them aggregation-prone. A range of hydrophobic precursor proteins that employ alternative, post-translational, routes for ER translocation also contribute to the cytosolic pool of mislocalized proteins (MLPs). In this review, we detail how mammalian cells can efficiently deal with these MLPs by selectively targeting them for proteasomal degradation. Strikingly, this pathway for MLP degradation is regulated by cytosolic components that also facilitate the TRC40-dependent, post-translational, delivery of tail-anchored membrane proteins (TA proteins) to the ER. Among these components are small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) and Bcl-2-associated athanogene 6 (BAG6), which appear to play a decisive role in enforcing quality control over hydrophobic precursor proteins that have mislocalized to the cytosol, directing them to either productive membrane insertion or selective ubiquitination and proteasomal degradation.
AB - A well-defined co-translational pathway couples the synthesis and translocation of nascent polypeptides into and across the membrane of the endoplasmic reticulum (ER), thereby minimizing the possibility of the hydrophobic signals and transmembrane domains that such proteins contain from being exposed to the cytosol. Nevertheless, a proportion of these co-translational substrates may fail to reach the ER, and therefore mislocalize to the cytosol where their intrinsic hydrophobicity makes them aggregation-prone. A range of hydrophobic precursor proteins that employ alternative, post-translational, routes for ER translocation also contribute to the cytosolic pool of mislocalized proteins (MLPs). In this review, we detail how mammalian cells can efficiently deal with these MLPs by selectively targeting them for proteasomal degradation. Strikingly, this pathway for MLP degradation is regulated by cytosolic components that also facilitate the TRC40-dependent, post-translational, delivery of tail-anchored membrane proteins (TA proteins) to the ER. Among these components are small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) and Bcl-2-associated athanogene 6 (BAG6), which appear to play a decisive role in enforcing quality control over hydrophobic precursor proteins that have mislocalized to the cytosol, directing them to either productive membrane insertion or selective ubiquitination and proteasomal degradation.
KW - Cellular targeting
KW - Proteasomes
KW - Protein quality control
KW - Ubiquitins
UR - http://www.scopus.com/inward/record.url?scp=85009761425&partnerID=8YFLogxK
U2 - 10.1042/BST20160045
DO - 10.1042/BST20160045
M3 - Review article
C2 - 27284044
AN - SCOPUS:85009761425
SN - 0300-5127
VL - 44
SP - 796
EP - 801
JO - Biochemical Society Transactions
JF - Biochemical Society Transactions
IS - 3
ER -