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

• 成果类型: Article
• 署名作者: Kulak, Klaudia; Kuska, Katarzyna; Colineau, Lucie; Mckay, Marina; Maziarz, Karolina; Slaby, Julia; Blom, Anna M.; King, Ben C.
• 署名单位: Lund University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13733
• DOI: 10.1073/pnas.2312621121
• 发表日期: 2024-02-20
• 关键词: complement c3; insulin-resistance; DOUBLE-BLIND; beta-cells; expression; il-1-beta; glucose; onset; interleukin-1; component

摘要

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-1 beta is a proinflammatory cytokine which detrimentally affects beta-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-1 beta treatment. In the current investigation, using primary human and rodent material and CRISPR/Cas9 gene- edited beta-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- 1 beta- induced beta-cell death, that is attributed to the cytosolic fraction of C3. Further investigation revealed that intracellular C3 alleviates IL- 1 beta- induced beta-cell death, by interaction with and inhibition of Fyn- related kinase (FRK), which is involved in the response of beta-cells to cytokines. Furthermore, these data were supported by increased beta-cell death in vivo in a beta- cell- specific C3 knockout mouse. Our data indicate that a functional, cytoprotective association exists between FRK and cytosolic C3.