Road to ruin: targeting proteins for degradation in the endoplasmic reticulum

Abstract

Some nascent proteins that fold within the endoplasmic reticulum (ER) never reach their native state. Misfolded proteins are removed from the folding machinery, dislocated from the ER into the cytosol, and degraded in a series of pathways collectively referred to as ER-associated degradation (ERAD). Distinct ERAD pathways centered on different E3 ubiquitin ligases survey the range of potential substrates. We now know many of the components of the ERAD machinery and pathways used to detect substrates and target them for degradation. Much less is known about the features used to identify terminally misfolded conformations and the broader role of these pathways in regulating protein half-lives.

Fig. 1

The events and components of ERAD. (A) The key steps of ERAD as shown for a luminal glycoprotein as applied to yeast or metazoans, and thus only the transmembrane E3 ubiquitin ligase complex is labeled along with its catalytic RING domain. (B) Overlapping substrate specificity of E3 ubiquitin ligases can be modulated by the presence of adaptors. Adaptors are depicted in purple and blue. (C) The core Hrd1p complex in yeast. (D) The core HRD1 complex in metazoans.

Fig. 2

Different paths that substrates take to the E3 complexes. (A) Delivery of correctly folded MHC class I molecules to the E3 by US11. (B) Cholesterol-regulated recognition of Hmg2p by the E3 complex. (C) Removal of a glycoprotein from the folding machinery, and modification of its glycans followed by processing by prodegradation factors and delivery to the E3 complex. (D) Reduction of substrate disulfide bonds by the EDEM1-ERdj5-BiP complex in metazoans in preparation for translocation.

Fig. 3

Targeting glycoproteins for degradation. (A) The initial high-mannose glycan appended to nascent polypeptides, Glc₃-Man₉-GlcNAc₂. (B) Metazoan glycan processing and delivery to the HRD1-ligase complex. (C) Luminal glycoprotein recognition by the Hrd3p-Yos9p complex in yeast. Only the complex in which Yos9p binds the glycan with the terminal α1,6-mannose linkage is capable of targeting substrates for degradation. In metazoan systems, it is thought that OS-9 may recognize glycans on SEL1L, as opposed to those on ERAD substrates, as discussed in the main text.