The E3 ubiquitin ligases Hrd1 and gp78 bind to and promote cholera toxin retro-translocation.

To cause disease, cholera toxin (CT) is transported from the cell surface to the endoplasmic reticulum (ER) lumen where the catalytic CTA1 subunit retro-translocates to the cytosol to induce pathological water secretion. Two retro-translocon components are the Derlins and ER-associated multi-spanning E3 ubiquitin ligases including Hrd1 and gp78. We demonstrated previously that Derlin-1 facilitates CTA1 retro-translocation.

Ubiquitination of MHC class I heavy chains is essential for dislocation by human cytomegalovirus-encoded US2 but not US11.

The human cytomegalovirus-encoded glycoproteins US2 and US11 target newly synthesized major histocompatibility complex class I heavy chains for degradation by mediating their dislocation from the endoplasmic reticulum back into the cytosol, where they are degraded by proteasomes. A functional ubiquitin system is required for US2- and US11-dependent dislocation of the class I heavy chains. It has been assumed that the class I heavy chain itself is ubiquitinated during the dislocation reaction.

The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway.

To eliminate misfolded proteins that accumulate in the endoplasmic reticulum (ER) the cell mainly relies on ubiquitin-proteasome dependent ER-associated protein degradation (ERAD). Proteolysis of ERAD substrates by the proteasome requires their ubiquitylation and retro-translocation from the ER to the cytoplasm. Here we describe a high molecular mass protein complex associated with the ER membrane, which facilitates ERAD.

Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane.

Misfolded proteins are eliminated from the endoplasmic reticulum (ER) by retrotranslocation into the cytosol, a pathway hijacked by certain viruses to destroy MHC class I heavy chains. The translocation of polypeptides across the ER membrane requires their polyubiquitination and subsequent extraction from the membrane by the p97 ATPase [also called valosin-containing protein (VCP) or, in yeast, Cdc48]. In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP).

Human cytomegalovirus-encoded US2 and US11 target unassembled MHC class I heavy chains for degradation.

Surface MHC class I molecules serve important immune functions as ligands for both T and NK cell receptors for the elimination of infected and malignant cells. In order to reach the cell surface, MHC class I molecules have to fold properly and form trimers consisting of a heavy chain (HC), a beta2-microglobulin light chain and an 8-10-mer peptide. A panel of ER chaperones facilitates the folding and assembly process.