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Deciphering the Role of Beta Cell ER Stress in Autoimmune Diabetes Pathogenesis
Feyza Engin1, Hugo Lee1, Gulcan Semra Sahin1, Chien-Wen Chen2, Shreyash Sonthalia1, Sandra Marín Cañas3, Hulya Zeynep Oktay1, Alexander T. Duckworth1, Maria Hatzoglou2, Decio L. Eizirik3.
1Department of Biomolecular Chemistry, University of Wisconsin-Madison.2Department of Genetics and Genome Sciences, Case Western Reserve University.3ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles
Background: Autoimmune-mediated β-cell destruction is the major cause of type 1 diabetes (T1D), yet the precise molecular mechanisms by which β-cells contribute to their own demise in T1D pathogenesis remain poorly understood. Until recently, it was thought that individuals with T1D had a total loss of insulin producing pancreatic β-cells. Recent evidence, however, has shown that patients with T1D, especially during the earlier phases of disease progression, retain some residual β-cells that express low levels of insulin. But how these β-cells survive the inflammatory and stressful islet microenvironment is unclear. Understanding the mechanisms of β-cell adaptation in the face of continued autoimmunity, which if it can be therapeutically targeted, has remarkable implications for the possible preservation of functional β-cell mass, and thus the slowing of disease progression and the improvement of disease management even without resorting to immunosuppressive agents. In addition, such insight may also lead to the identification of similar pathways that can be targeted to improve outcome in other autoimmune diseases. One form of cellular stress is ER stress, and a well-studied response to it is the unfolded protein response (UPR). Work from our group (Engin et al, Sci Transl Med, 2013, Lee et al., Cell Metab, 2020, Chen et al., Nat Comm, 2022) and others have indicated the role of β-cell ER stress and dysregulated UPR in the development of T1D in mice and in humans. However, currently, a major obstacle in the field is the lack of in vivo preclinical models to unravel the adaptive or maladaptive mechanisms of ER stress and their regulation in stressed β-cells.
Aims: Identifying the β-cell-specific function of ATF6 in a preclinical T1D model and human islets.
Methods: Our study combines tissue-specific knockout mouse models, mouse and human β-cell lines, and primary islets from human donors and individuals with T1D, as well as single cell RNA-sequencing in mouse and human islets to support our mechanistic model.
Results: Using a recently generated mouse model, we made the striking discovery that activating transcription factor 6 (Atf6), a key UPR sensor that can activate or repress transcription, functions as a negative regulator of a previously not recognized pro-survival adaptative program in β-cells during T1D progression. Our data show that deletion of Atf6 in β-cells of a well-established T1D model, non-obese diabetic (NOD) mice (Atf6 β-/-), prior to insulitis, leads to significantly reduced diabetes incidence. Transcriptome analysis of sorted β-cells of Atf6β-/- mice revealed p53/p21 signaling pathway as the top enriched pathway. The significantly increased expression of (i) p21 and its downstream target genes mediating anti-oxidant and DNA damage responses (DDR) and (ii) immune inhibitory markers was consistent with markedly reduced insulitis and β-cells apoptosis observed in Atf6β-/- mice. through single cell analysis we identified the conserved transcriptome of this new adaptive program in residual beta cells of individuals with T1D.
Conclusions: Collectively, these data suggest that Atf6 elicits a maladaptive response in T1D, and its loss-of-function incites an unexpected multipronged stress adaptation program in β-cells, which ultimately confers protection from T1D.
This study was supported by grants from the National Institute of Health (DK130919 and DK128136), Grater Milwaukee Foundation, and startup funds from the University of Wisconsin-Madison, and NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH Grant # U24DK098085 and the JDRF-funded IIDP Islet Award Initiative.