Fasana, ElisaFregno, IlariaGalli, CarmelaSolda, TatianaMolinari, Maurizio2024-06-052024-06-052024-06-052024-05-2110.1038/s44319-024-00165-yhttps://infoscience.epfl.ch/handle/20.500.14299/208432WOS:001228805800002The endoplasmic reticulum (ER) produces proteins destined to organelles of the endocytic and secretory pathways, the plasma membrane, and the extracellular space. While native proteins are transported to their intra- or extracellular site of activity, folding-defective polypeptides are retro-translocated across the ER membrane into the cytoplasm, poly-ubiquitylated and degraded by 26 S proteasomes in a process called ER-associated degradation (ERAD). Large misfolded polypeptides, such as polymers of alpha1 antitrypsin Z (ATZ) or mutant procollagens, fail to be dislocated across the ER membrane and instead enter ER-to-lysosome-associated degradation (ERLAD) pathways. Here, we show that pharmacological or genetic inhibition of ERAD components, such as the alpha 1,2-mannosidase EDEM1 or the OS9 ERAD lectins triggers the delivery of the canonical ERAD clients Null Hong Kong (NHK) and BACE457 Delta to degradative endolysosomes under control of the ER-phagy receptor FAM134B and the LC3 lipidation machinery. Our results reveal that ERAD dysfunction is compensated by the activation of FAM134B-driven ERLAD pathways that ensure efficient lysosomal clearance of orphan ERAD clients.|Misfolded polypeptides from the Endoplasmic reticulum (ER) are either cleared via the proteasomal ER-Associated-Degradation (ERAD) or the lysosomal ER-to-Lysosome-Associated-Degradation (ERLAD) pathway. Here, genetic- or pharmacologically-induced ERAD dysfunction is shown to activate compensatory ERLAD programs.ERAD dysfunction activates ERLAD pathways to ensure efficient clearance of misfolded polypeptides and maintain ER homeostasis. Failsafe ERLAD pathways for the model polypeptides NHK and BACE457 Delta rely on the ER-phagy receptor FAM134B and the LC3 lipidation machinery. Compensatory ERLAD pathways may involve other ER-phagy receptors (e.g., CCPG1, FAM134B-2) for other clients or tissue-specific programs.|ERAD dysfunction activates compensatory ERLAD programs to clear misfolded ER proteins.Life Sciences & BiomedicineEndoplasmic Reticulum (Er)Er-Associated Degradation (Erad)Er-To-Lysosome-Associated Degradation (Erlad)Er-PhagyProtein Quality Controltext::journal::journal article::research article