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

Klaudia Kulak, Katarzyna Kuska, Lucie Colineau, Marina Mckay, Karolina Maziarz, Julia Slaby, Anna M Blom, Ben C King

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere2312621121
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number8
DOIs
Publication statusPublished - 2024 Feb 12

Subject classification (UKÄ)

  • Endocrinology and Diabetes
  • Cell and Molecular Biology

Free keywords

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

Fingerprint

Dive into the research topics of 'Intracellular C3 protects β-cells from IL-1β-driven cytotoxicity via interaction with Fyn-related kinase'. Together they form a unique fingerprint.

Cite this