Protein quality control in the endoplasmic reticulum

Abstract

Summary Misfolded and mistargeted proteins in the early secretory pathway present significant risks to the cell. A diverse and integrated network of quality control pathways protects the cell from these threats. We focus on the discovery of new mechanisms that contribute to this protective network. Biochemical and structural advances in endoplasmic reticulum targeting fidelity, and in the redistribution of mistargeted substrates are discussed. We further review new discoveries in quality control at the inner nuclear membrane in the context of orphaned subunits. We consider developments in our understanding of cargo selection for endoplasmic reticulum export. Conflicting data on quality control by cargo receptor proteins are discussed and we look to important future questions for the field.

Pathological turret mutations in the cardiac sodium channel cause long-range pore disruption

“…The previously reported human D1430N BrS-associated null-mutant is similarly expressed on the plasma membrane (12). There are multiple and extensive quality-control mechanisms within the secretory pathway that can efficiently detect and destroy aberrantly-folded proteins before they reach the plasma membrane (33). Hence, the compromised gating behavior of the mutant Nav1.5 channels is unlikely to be explained by a large-scale misfolding of the channels.…”

Cellular Dynamics of Transition Metal Exchange on Proteins: A Challenge but a Bonanza for Coordination Chemistry

“…Therefore, metal delivery systems probably have time to act on nascent proteins before disulfide bridges are formed. In eukaryotes, quality control and addressing mechanisms are coordinated and act on active ribosomes to avoid waste of cellular resources and potential toxic effects of deficient translation and translocation [ 68 , 69 ]. How metalloproteins balance the function of these complex and successive monitoring systems with incorporation of metals or metal prosthetic groups is presently a fully open question.…”

Editorial overview: Membrane traffic in the time of COVID-19

“…The recent progress in understanding regulation of clathrin-coated vesicle formation reviewed by Briant et al [2] demonstrates how clathrin-mediated pathways affect tissue development and differentiation, as well as disease. The review by Phillips et al [18] discusses quality control mechanisms in the endoplasmic reticulum that are absolutely critical for the health of a cell and whose malfunction accounts for toxicity in protein folding diseases. The formation of protein sorting domains and tubules on endosomes for selective degradation or recycling is emerging as a key mechanism of cargo sorting, as described at the molecular and structural levels in the review by Weeratunga et al [19] and as reviewed for the endosomal pathway of C. elegans by Norris and Grant [20].…”