干旱区生态环境知识资源中心(Arid): Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co- ordinating insulin biosynthesis with secretory granule formation

Arid

DOI	10.1016/j.molmet.2023.101845
	Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co- ordinating insulin biosynthesis with secretory granule formation
	Sue, Nancy; Thai, Le May; Saito, Atsushi; Boyer, Cierra K.; Fordham, Ashleigh M.; Yan, Chenxu; Davenport, Aimee; Tao, Jiang; Bensellam, Mohammed; Cantley, James; Shi, Yan-Chuan; Stephens, Samuel B.; Imaizumi, Kazunori; Biden, Trevor J.
通讯作者	Biden, TJ
来源期刊	MOLECULAR METABOLISM
ISSN	2212-8778
出版年	2024
卷号	79
英文摘要	Objective: Although individual steps have been characterized, there is little understanding of the overall process whereby glucose co-ordinates the biosynthesis of insulin with its export out of the endoplasmic reticulum (ER) and incorporation into insulin secretory granules (ISGs). Here we investigate a role for the transcription factor CREB3L2 in this context.Methods: MIN6 cells and mouse islets were analysed by immunoblotting after treatment with glucose, fatty acids, thapsigargin and various inhibitors. Knockdown of CREB3L2 was achieved using si or sh constructs by transfection, or viral delivery. In vivo metabolic phenotyping was conducted after deletion of CREB3L2 in beta-cells of adult mice using Ins1-CreER(+). Islets were isolated for RNAseq and assays of glucose-stimulated insulin secretion (GSIS). Trafficking was monitored in islet monolayers using a GFP-tagged proinsulin construct that allows for synchronised release from the ER.Results: With a K-m approximate to 3.5 mM, glucose rapidly (T-1/2 0.9 h) increased full length (FL) CREB3L2 followed by a slower rise (T-1/2 2.5 h) in its transcriptionally-active cleavage product, P60 CREB3L2. Glucose stimulation repressed the ER stress marker, CHOP, and this was partially reverted by knockdown of CREB3L2. Activation of CREB3L2 by glucose was not due to ER stress, however, but a combination of O-GlcNAcylation, which impaired proteasomal degradation of FL-CREB3L2, and mTORC1 stimulation, which enhanced its conversion to P60. cAMP generation also activated CREB3L2, but independently of glucose. Deletion of CREB3L2 inhibited GSIS ex vivo and, following a high-fat diet (HFD), impaired glucose tolerance and insulin secretion in vivo. RNAseq revealed that CREB3L2 regulated genes controlling trafficking to-and-from the Golgi, as well as a broader cohort associated with beta-cell compensation during a HFD. Although post-Golgi trafficking appeared intact, knockdown of CREB3L2 impaired the generation of both nascent ISGs and proinsulin condensates in the Golgi, implying a defect in ER export of proinsulin and/or its processing in the Golgi.Conclusion: The stimulation of CREB3L2 by glucose defines a novel, rapid and direct mechanism for co-ordinating the synthesis, packaging and storage of insulin, thereby minimizing ER overload and optimizing beta-cell function under conditions of high secretory demand. Upregulation of CREB3L2 also potentially contributes to the benefits of GLP1 agonism and might in itself constitute a novel means of treating beta-cell failure.Crown Copyright (c) 2023 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
英文关键词	Pancreatic beta-cell Insulin biosynthesis Insulin secretion O-GlcNAcylation ER stress ER-to-Golgi trafficking
类型	Article
语种	英语
开放获取类型	gold
收录类别	SCI-E
WOS记录号	WOS:001135411200001
WOS关键词	ENDOPLASMIC-RETICULUM STRESS ; UNFOLDED PROTEIN RESPONSE ; BBF2H7-MEDIATED SEC23A PATHWAY ; OASIS FAMILY ; ER STRESS ; TRAFFICKING ; CONTRIBUTES ; DYSFUNCTION ; MECHANISMS ; EXPRESSION
WOS类目	Endocrinology & Metabolism
WOS研究方向	Endocrinology & Metabolism
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/404932
推荐引用方式 GB/T 7714	Sue, Nancy,Thai, Le May,Saito, Atsushi,et al. Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co- ordinating insulin biosynthesis with secretory granule formation[J],2024,79.
APA	Sue, Nancy.,Thai, Le May.,Saito, Atsushi.,Boyer, Cierra K..,Fordham, Ashleigh M..,...&Biden, Trevor J..(2024).Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co- ordinating insulin biosynthesis with secretory granule formation.MOLECULAR METABOLISM,79.
MLA	Sue, Nancy,et al."Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co- ordinating insulin biosynthesis with secretory granule formation".MOLECULAR METABOLISM 79(2024).