Integration of ER protein quality control mechanisms defines β-cell function and ER architecture.
“Integration Of Er Protein Quality Control Mechanisms Defines Β-Cell Function And Er Architecture.”. The Journal Of Clinical Investigation..
|Center||University of Michigan|
|Author||Neha Shrestha, Mauricio Torres, Jason Zhang, You Lu, Leena Haataja, Rachel B Reinert, Jeffrey Knupp, Yu-Jie Chen, Günes Parlakgül, Ana Paula Arruda, Billy Tsai, Peter Arvan, Ling Qi|
|Keywords||Autophagy, Cell Biology, diabetes, Metabolism, Protein misfolding|
Three principal ER quality-control mechanisms, namely, unfolded protein response (UPR), 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 three 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 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 autophagy in β-cells leads to diabetes in mice shortly after weaning, with premature death by ~11 weeks of age, associated with marked ER retention of proinsulin and β-cell loss. Using focus-ion beam scanning electron microscopy (FIB-SEM) powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β-cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the three ER quality-control mechanisms in the dynamic regulation of organellar architecture and β-cell function.
|Year of Publication||
The Journal of clinical investigation
J Clin Invest