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Integration of ER protein quality-control mechanisms defines β cell function and ER architecture
Neha Shrestha, … , Peter Arvan, Ling Qi
Neha Shrestha, … , Peter Arvan, Ling Qi
Published November 8, 2022
Citation Information: J Clin Invest. 2023;133(1):e163584. https://doi.org/10.1172/JCI163584.
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Research Article Cell biology Metabolism

Integration of ER protein quality-control mechanisms defines β cell function and ER architecture

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Abstract

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 autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy 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 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.

Authors

Neha Shrestha, Mauricio Torres, Jason Zhang, You Lu, Leena Haataja, Rachel B. Reinert, Jeffrey Knupp, Yu-Jie Chen, Allen H. Hunter, Gunes Parlakgul, Ana Paula Arruda, Billy Tsai, Peter Arvan, Ling Qi

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Figure 6

ERAD and autophagy synergistically determine the ER architecture in β cells.

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ERAD and autophagy synergistically determine the ER architecture in β ce...
(A) Immunoblot of ER sheet and tubule markers. (B) Quantification of results in A; n = 3 mice per genotype. Values are shown as mean ± SEM. *P < 0.05, ****P < 0.0001 by 1-way ANOVA with Tukey’s post hoc test. (C) Magnified view of the ER (3 μm × 3 μm × 3 μm cubic volume) in each genotype. (D) Magnified view of the of the ER (x-y plane), highlighting the size of ER lumen. (E) Magnified view of the ER (y-z plane). Arrow indicates ER sheets. (F) 3D reconstruction of the fraction of ER lumen highlighting ER networks (2 μm × 2 μm × 1 μm), with individual ER networks in distinct colors.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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