Intracellular C3 protects β-cells from IL-1β-driven cytotoxicity via interaction with Fyn-related kinase.

Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE

Original Publication: Washington, DC : National Academy of Sciences

Diabetes Mellitus, Type 2*/metabolism ; Insulin-Secreting Cells*/metabolism ; Islets of Langerhans*/metabolism; Mice ; Animals ; Humans ; Cell Death ; Cytokines/metabolism ; Mice, Knockout

One of the hallmarks of type 1 but also type 2 diabetes is pancreatic islet inflammation, associated with altered pancreatic islet function and structure, if unresolved. IL-1β is a proinflammatory cytokine which detrimentally affects β-cell function. In the course of diabetes, complement components, including the central complement protein C3, are deregulated. Previously, we reported high C3 expression in human pancreatic islets, with upregulation after IL-1β treatment. In the current investigation, using primary human and rodent material and CRISPR/Cas9 gene-edited β-cells deficient in C3, or producing only cytosolic C3 from a noncanonical in-frame start codon, we report a protective effect of C3 against IL-1β-induced β-cell death, that is attributed to the cytosolic fraction of C3. Further investigation revealed that intracellular C3 alleviates IL-1β-induced β-cell death, by interaction with and inhibition of Fyn-related kinase (FRK), which is involved in the response of β-cells to cytokines. Furthermore, these data were supported by increased β-cell death in vivo in a β-cell-specific C3 knockout mouse. Our data indicate that a functional, cytoprotective association exists between FRK and cytosolic C3.
Competing Interests: Competing interests statement:The authors declare no competing interest.

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Wallenberg Scholar Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation); N/A Diabetesfonden (Stiftelsen Svenska Diabetesförbundets Forskningsfond); IRC15-0067 Stiftelsen för Strategisk Forskning (SSF); 2022-00532 Vetenskapsrådet (VR); 2009-1039 Vetenskapsrådet (VR); N/A Direktör Albert Påhlssons Stiftelse (Påhlssons Stiftelse); N/A Magnus Bergvalls Stiftelse (Magnus Bergvall Foundation); N/A Crafoordska Stiftelsen (The Crafoord Foundation); N/A Bo and Kerstin Hjelt Diabetes Foundation (Diabetes Foundation); N/A Governmental grant for clinical research (ALF)

Keywords: C3; FRK; IL-1β; diabetes; β-cell

0 (Cytokines)

Date Created: 20240212 Date Completed: 20240214 Latest Revision: 20240228

20240228

PMC10895342

10.1073/pnas.2312621121

38346191