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TSC22D1 is a newly identiﬁed inhibitor of insulinsecretion in pancreatic beta cells

ABSTRACT: The loss of pancreatic beta cell function leads to chronically high blood glucose levels, contributing to diabetes mellitus, one of the leading causes of morbidity and mortality worldwide. Understanding the molecular mechanisms that regulate beta cell function could pave the way for the development of more effective anti-diabetic treatments. In this study, we identify the evolutionarily conserved TSC22D1 protein as a novel regulator of beta cell function. TSC22D1 depletion in INS-1E cells enhances the expression of beta cell identity genes, including Ins1, Ins2, Pdx1, Slc2a2, and Nkx6.1 and promotes glucose-stimulated insulin secretion without altering intracellular insulin content. Mechanistically, TSC22D1 and FoxO1 interact and regulate each other reciprocally to control beta cell function. Our follow-up interactome analysis revealed other novel proteins that differentially bind to TSC22D1 depending on glucose availability. These include several RNA-binding proteins such as Hnrnpm and Ddx46, as well as distinct tubulin isoforms, chaperones, and Scgn, a well-known regulator of insulin secretion. To further investigate the impact of TSC22D1 deficiency in cellular response to glucose stimulation, we performed RNA sequencing (RNA-Seq) experiment. The RNA-Seq results strongly aligned with our mass spectrometry interactome data and revealed mRNA processing, ribonucleoprotein complex biogenesis, and Golgi vesicle transport within the top pathways that are enriched upon glucose stimulation in TSC22D1 deficient cells. Overall, our study confirms that beta cell function requires tight regulation of insulin synthesis and secretion at multiple levels, even by a single protein, which we identified as TSC22D1, further highlighting the potential of targeting TSC22D1 in the development of new therapeutic strategies for diabetes.

INSTRUMENT(S):

ORGANISM(S): Rattus Rattus (black Rat)

TISSUE(S): Pancreatic Islet Beta Cell

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Ann-Christine König

LAB HEAD: Bilgen Ekim

PROVIDER: PXD054957 | Pride | 2025-08-25

REPOSITORIES: Pride

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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TSC22D1 is a newly identiﬁed inhibitor of insulinsecretion in pancreatic beta cells

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