ER-associated degradation articles from across Nature Portfolio

Doa10/MARCHF6 is a conserved E3 ubiquitin ligase in the endoplasmic reticulum (ER) membrane in eukaryotes, but its molecular mechanism was unknown. The authors combine cryo-EM, computational and biochemical analyses to reveal how Doa10 recognizes its substrate proteins for ER-associated degradation.

Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that primarily responds to ligation of bacterial lipopolysaccharide. Here the authors suggest the intramembrane protease RHBDL4 as a regulator of TLR4 signaling.

The importance of the SEL1L-HRD1 interaction in vivo was unclear. Here, authors reported that SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex by recruiting the E2 enzyme UBE2J1 and DERLIN to HRD1.

The stoichiometry of Hrd1, an integral membrane E3 ubiquitin ligase is critical to maintaining proteostasis in the endoplasmic reticulum. Here, the authors establish a single-molecule counting approach coupled with a single-molecule in vitro ubiquitination system to determine the functional stoichiometry of Hrd1.

The nature of SEL1L-HRD1 ERAD substrates remains unclear. Here, the authors identified ~100 endogenous substrates, and showed that SEL1L-HRD1 ERAD is indispensable for the activity of GPI transamidase complex and the biogenesis of GPI-anchored proteins.

Endoplasmic reticulum-associated protein degradation (ERAD) enables removal of aberrant or surplus proteins from the ER. ERAD represents a collection of independent processes exhibiting distinct yet overlapping selectivity for a wide range of substrates, enabling efficient quality control of membrane and secretory proteins.

Hrd1 may form a channel regulated by autoubiquitylation that has a major role in translocating misfolded proteins from the ER lumen to the cytoplasm for subsequent degradation.

Clearing misfolded proteins from the cytoplasm is essential to maintain cellular homeostasis. Now, a parallel clearance system is described that uses the deubiquitylase USP19 to enable secretion of misfolded cytoplasmic proteins when conventional proteasomal degradation is compromised. Misfolding-associated protein secretion (MAPS) has important implications for protein quality control and prion-like transmission.

The Asi complex defines an ERAD branch that is specific for inner nuclear membrane protein quality control in yeast.