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Abstract
The maintenance of endoplasmic reticulum (ER) homeostasis is essential for cell function. ER stress-induced pre-emptive quality control (ERpQC) helps alleviate the burden to a stressed ER by limiting further protein loading. We have previously reported the mechanisms of ERpQC, which includes a rerouting step and a degradation step. Under ER stress conditions, Derlin family proteins (Derlins), which are components of ER-associated degradation, reroute specific ER-targeting proteins to the cytosol. Newly synthesized rerouted polypeptides are degraded via the cytosolic chaperone Bag6 and the AAA-ATPase p97 in the ubiquitin-proteasome system. However, the mechanisms by which ER-targeting proteins are rerouted from the ER translocation pathway to the cytosolic degradation pathway and how the E3 ligase ubiquitinates ERpQC substrates remain unclear. Here, we show that ERpQC substrates are captured by the carboxyl-terminus region of Derlin-1 and ubiquitinated by the HRD1 E3 ubiquitin ligase prior to degradation. Moreover, HRD1 forms a large ERpQC-related complex composed of Sec61α and Derlin-1 during ER stress. These findings indicate that the association of the degradation factor HRD1 with the translocon and the rerouting factor Derlin-1 may be necessary for the smooth and effective clearance of ERpQC substrates.
Highlights
In co-translational translocation, secretory and transmembrane proteins possessing signal sequences or transmembrane domains are targeted to the endoplasmic reticulum (ER) membrane and translocated into the ER via the docking of a ribosome to the translocon
We previously studied the mechanism of ER stress-induced pQC (ERpQC), which controls protein loading into the ER through Derlinmediated rerouting from the ER to the cytosol prior to proteasomal degradation[5]
In wild-type (WT) HEK293 cells treated with the ER stressor thapsigargin (Tg) and a proteasome inhibitor (MG132), the accumulation of signal peptide-uncleaved NHKQQQ (SNHKQQQ, an ERpQC substrate) was observed (Supplementary Fig. 1a, top panel, lane 3, arrowhead), but this form was absent from Derlin family proteins (Derlins)-1 knockout (Derl[1] KO) HEK 293 cells (Supplementary Fig. 1a, top panel, lane 7), consistent with our previous study[5]
Summary
In co-translational translocation, secretory and transmembrane proteins possessing signal sequences or transmembrane domains are targeted to the ER membrane and translocated into the ER via the docking of a ribosome to the translocon. ER stress-induced pQC (ERpQC) is thought to occur as follows[1,3,4]: (1) in co-translational translocation, the hydrophobic signal peptide of nascent polypeptides that emerges from the ribosome is recognized by the signal recognition particle (SRP); (2) the ribosome nascent chain (RNC)-SRP complex is targeted to the translocon; (3) the translocation of specific ER proteins is attenuated by an unknown mechanism during ER stress; (4) translationally and translocationally attenuated nascent chains are released from the translocon; and (5) the fully translated proteins in the cytosol are degraded by the UPS This pre-emptive degradation system restricts excessive protein loading into the ER and protects cells against ER stress. Association of the translocon, Derlin-1, and HRD1 may compose a hub of the ERpQC machinery
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