Intracellular C3 protects β-cells from IL-1β-driven cytotoxicity via interaction with Fyn-related kinase
Kulak, Klaudia LU ; Kuska, Katarzyna LU ; Colineau, Lucie LU ; Mckay, Marina LU ; Maziarz, Karolina LU
; Slaby, Julia
LU
; Blom, Anna M
LU
and King, Ben C
LU
(2024)
In Proceedings of the National Academy of Sciences of the United States of America
121(8).
- 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,... (More)
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.
(Less)
- author
- Kulak, Klaudia
LU
; Kuska, Katarzyna
LU
; Colineau, Lucie
LU
; Mckay, Marina
LU
; Maziarz, Karolina
LU
; Slaby, Julia
LU
; Blom, Anna M
LU
and King, Ben C
LU
- organization
- publishing date
- 2024-02-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Mice, Animals, Humans, Diabetes Mellitus, Type 2/metabolism, Insulin-Secreting Cells/metabolism, Islets of Langerhans/metabolism, Cell Death, Cytokines/metabolism, Mice, Knockout
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 121
- issue
- 8
- article number
- e2312621121
- pages
- 11 pages
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:85185114312
- pmid:38346191
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.2312621121
- language
- English
- LU publication?
- yes
- id
- aa2bd38d-a2e7-444d-9d87-73c6765d7dac
- date added to LUP
- 2024-02-21 14:31:00
- date last changed
- 2024-04-21 19:39:50
@article{aa2bd38d-a2e7-444d-9d87-73c6765d7dac,
abstract = {{<p>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.</p>}},
author = {{Kulak, Klaudia and Kuska, Katarzyna and Colineau, Lucie and Mckay, Marina and Maziarz, Karolina and Slaby, Julia and Blom, Anna M and King, Ben C}},
issn = {{1091-6490}},
keywords = {{Mice; Animals; Humans; Diabetes Mellitus, Type 2/metabolism; Insulin-Secreting Cells/metabolism; Islets of Langerhans/metabolism; Cell Death; Cytokines/metabolism; Mice, Knockout}},
language = {{eng}},
month = {{02}},
number = {{8}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Intracellular C3 protects β-cells from IL-1β-driven cytotoxicity via interaction with Fyn-related kinase}},
url = {{http://dx.doi.org/10.1073/pnas.2312621121}},
doi = {{10.1073/pnas.2312621121}},
volume = {{121}},
year = {{2024}},
}