A tandem-fluorescent reporter consisting of a HaloTag-GFP chimera appended at the C- or at the N-terminus of select polypeptides to monitor protein and organelle delivery to the lysosomal district in a quantitative and time-resolved manner

Conserved catabolic pathways operate to remove aberrant polypeptides from the endoplasmic reticulum (ER), the major biosynthetic organelle of eukaryotic cells. The best known are the ER‐associated degradation (ERAD) pathways that control the retrotranslocation of terminally misfolded proteins across the ER membrane for clearance by the cytoplasmic ubiquitin/proteasome system. In this review, we catalog folding‐defective mammalian, yeast, and plant proteins that fail to engage ERAD machineries. We describe that they rather segregate in ER subdomains that eventually vesiculate. These ER‐derived vesicles are captured by double membrane autophagosomes, engulfed by endolysosomes/vacuoles, or fused with degradative organelles to clear cells from their toxic cargo. These client‐specific, mechanistically diverse ER‐phagy pathways are grouped under the umbrella term of ER‐to‐lysosome‐associated degradation for description in this essay.

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