biostudies-literatureShrestha NNIDDKe163584https://www.ebi.ac.uk/biostudies/studies/S-EPMC9797341biostudies-literatureUnknown133(1)Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and aThe Journal of clinical investigationIntegration of ER protein quality control mechanisms defines β cell function and ER architecture.PMC9797341R01DK111174Torres MQi LZhang JReinert RBLu YArvan PParlakgul GHaataja LTsai BKnupp JShrestha NChen YJArruda APfalseIntegration of ER protein quality control mechanisms defines β cell function and ER architecture.Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and a2023-01-01T00:00:00Z2023 Jan2025-04-04T19:09:03.223Z2025-04-04T19:09:03.223ZS-EPMC97973413634667110.1172/JCI163584