About 40% of the eukaryotic cell’s proteins are inserted co- or post-translationally in the endoplasmic reticulum (ER), where they attain the native structure under the assistance of resident molecular chaperones and folding enzymes. Subsequently, these proteins are secreted from cells or are transported to their sites of function at the plasma membrane or in organelles of the secretory and endocytic compartments. Polypeptides that are not delivered within the ER (mis-localized proteins, MLPs) are rapidly destroyed by cytosolic proteasomes, with intervention of the membrane protease ZMPSTE24 if they remained trapped in the SEC61 translocation machinery. Proteins that enter the ER, but fail to attain the native structure are rapidly degraded to prevent toxic accumulation of aberrant gene products. The ER does not contain degradative devices and the majority of misfolded proteins generated in this biosynthetic compartment are dislocated across the membrane for degradation by cytosolic 26S proteasomes by mechanisms and pathways collectively defined as ER-associated degradation (ERAD). Proteins that do not engage ERAD factors, that enter aggregates or polymers, are too large, display chimico/physical features that prevent dislocation across the ER membrane (ERAD-resistant misfolded proteins) are delivered to endo-lysosome for clearance, by mechanisms and pathways collectively defined as ER-to-lysosomes-associated degradation (ERLAD). Emerging evidences lead us to propose ERLAD as an umbrella term that includes the autophagic and non-autophagic pathways activated and engaged by ERAD-resistant misfolded proteins generated in the ER for delivery to degradative endo-lysosomes.

大约40％的真核细胞蛋白共翻译或翻译后插入内质网（ER），在内质网分子伴侣和折叠酶的帮助下它们达到天然结构。随后，这些蛋白质从细胞中分泌出来，或在质膜上或在分泌和内吞区室的细胞器中转运到它们的功能位点。尚未在ER内传递的多肽（定位错误的蛋白质，MLP）会被胞浆蛋白酶迅速破坏，如果仍被膜蛋白酶ZMPSTE24困在SEC61易位机制中，则它们会受到膜蛋白酶ZMPSTE24的干预。进入内质网但未能获得天然结构的蛋白质会迅速降解，以防止异常基因产物的毒性积累。ER不包含降解装置，并且在该生物合成区室中产生的大多数错误折叠的蛋白质都跨膜错位分布，以通过胞质26S蛋白酶体通过统称为ER相关降解（ERAD）的机制和途径进行降解。不参与ERAD因子而进入聚集体或聚合物的蛋白质太大，显示出防止通过ER膜错位的化学/物理特征（ERAD抗性折叠错误的蛋白质）通过机制和途径被传递至内溶酶体进行清除。 ER到溶酶体相关的降解（ERLAD）统称为。