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Intracellular C3 protects β-cells from IL-1β-driven cytotoxicity via interaction with Fyn-related kinase.
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- Author(s): Kulak K;Kulak K; Kuska K; Kuska K; Colineau L; Colineau L; Mckay M; Mckay M; Maziarz K; Maziarz K; Slaby J; Slaby J; Blom AM; Blom AM; King BC; King BC
- Source:
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Feb 20; Vol. 121 (8), pp. e2312621121. Date of Electronic Publication: 2024 Feb 12.- Publication Type:
Journal Article- Language:
English - Source:
- Additional Information
- Source: 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
- Publication Information: Original Publication: Washington, DC : National Academy of Sciences
- Subject Terms:
- Abstract: 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.
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Science. 2005 Feb 18;307(5712):1098-101. (PMID: 15718470) - Grant Information: 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)
- Contributed Indexing: Keywords: C3; FRK; IL-1β; diabetes; β-cell
- Accession Number: 0 (Cytokines)
- Publication Date: Date Created: 20240212 Date Completed: 20240214 Latest Revision: 20240228
- Publication Date: 20240228
- Accession Number: PMC10895342
- Accession Number: 10.1073/pnas.2312621121
- Accession Number: 38346191
- Source:
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