GRP94 Is an Essential Regulator of Pancreatic β-Cell Development, Mass, and Function in Male Mice

Kim, Do-sung; Song, Lili; Wang, Jingjing; Wu, Hongju; Gu, Guoqiang; Sugi, Yukiko; Li, Zihai; Wang, Hongjun

doi:10.1210/en.2017-00685

Cited by 24 publications

(36 citation statements)

References 56 publications

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“…Recently, GRP94 has been shown to be essential for β-cell development in that β-cell–specific GRP94 KO mice exhibit pancreatic hypoplasia and reduced β-cell proliferation and mass ( 20 ). These mice remained euglycemic but had impaired glucose tolerance, reduced serum insulin and insulin mRNA expression at embryonic day 14.5, an increased number of amorphous secretory granules (nonquantified), and distended ER in EM.…”

Section: Discussionmentioning

confidence: 99%

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Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential for Proinsulin Handling

et al. 2019

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Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is underinvestigated. Here, we have explored the importance of glucose-regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within b-cells. We found that GRP94 coimmunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucosedependent insulin secretion, shortened proinsulin half-life, and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by postER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in b-cells selectively activated protein kinase R-like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.

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Section: Discussionmentioning

confidence: 99%

“…GRP94 ATPase activity ( 17 ) is inhibited by geldanamycin ( 18 ) or newly developed GRP94-specific inhibitors ( 19 ). Recently, GRP94 has been ablated in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells and shown to be an essential regulator of β-cell development, mass, and function ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential for Proinsulin Handling

et al. 2019

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“…In agreement with these facts, GRP94 has been found critical for regulation and development of pancreatic β-Cells providing new insights for preservation enhancement of β-cell function. [ 252 ].…”

Section: Role Of Hsp90 Isoforms In Pathological Conditionsmentioning

confidence: 99%

The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease

Hoter

El-Sabban

Naim³

2018

IJMS

448

363

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The mammalian HSP90 family of proteins is a cluster of highly conserved molecules that are involved in myriad cellular processes. Their distribution in various cellular compartments underlines their essential roles in cellular homeostasis. HSP90 and its co-chaperones orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis. Conversely, HSP90, and its secreted forms, contribute to the development and progress of serious pathologies, including cancer and neurodegenerative diseases. Therefore, targeting HSP90 is an attractive strategy for the treatment of neoplasms and other diseases. This manuscript will review the general structure, regulation and function of HSP90 family and their potential role in pathophysiology.

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“…Affinity purification of proCpepAPEX2 biotinylated proteins (Fig. 3c) revealed interactions with the ER resident chaperone, GRP94, and granin protein, CgB, which have both been demonstrated to regulate proinsulin trafficking 21,25,26 . In contrast, no labeling of the plasma membrane SNARE, syntaxin-4, was observed, as expected.…”

Section: Resultsmentioning

confidence: 99%

Nutrient metabolism regulates insulin granule formation in the pancreatic islet β-cell via ER redox homeostasis

Rohli

Boyer

Bearrows

et al. 2021

Preprint

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Defects in the β-cells secretion system are well-described in Type 2 diabetes (T2D), including reduced insulin storage and impaired proinsulin processing; however, the cellular mechanisms underlying these secretory defects and the contribution of chronic hyperglycemia to this process remain poorly understood. In this study, we provide evidence that oxidative protein folding in the endoplasmic reticulum (ER) is perturbed in models of β-cell dysfunction, leading to delays in proinsulin trafficking and insulin granule formation. Using an in situ fluorescent pulse-chase labeling strategy and APEX2-based proximity labeling, we demonstrate that enriched interactions of proinsulin with ER oxidoreductases coincides with a delay in proinsulin ER export. Furthermore, our data show that proinsulin ER export can be regulated by metabolically-derived NADPH and reducing equivalent (glutathione) availability. Together, these data highlight an emerging role for nutrient metabolism and mitochondrial dysfunction in the maladaptive remodeling of the β-cells secretory pathway during the decline of β-cell function in T2D.

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GRP94 Is an Essential Regulator of Pancreatic β-Cell Development, Mass, and Function in Male Mice

Cited by 24 publications

References 56 publications

Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential for Proinsulin Handling

Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential for Proinsulin Handling

The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease

Nutrient metabolism regulates insulin granule formation in the pancreatic islet β-cell via ER redox homeostasis

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