Ribosomes synthesise secretory proteins into the endoplasmic reticulum (ER) lumen. Chaperones (green) promote proper folding of nascent proteins and refolding of damaged secretory proteins (orange). Build-up of damaged proteins in the ER activates a signalling cascade called the ER unfolded protein response (UPRER) that upregulates the expression of specific gene products to restore proper folding balance and ensure the quality and secretion of properly folded proteins (purple). Outside the cell, extracellular regulators (ECRs, brown) bind to misfolded proteins, preventing aggregation and promoting clearance by endocytosis followed by lysosomal degradation. Data presented here suggest the existence of an ER-like surveillance of extracellular protein quality that conveys extracellular damage to the nucleus via immune pathways to increase expression of ECR gene products.