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Intracellular C3 regulates the immune response to infection via NF-κB signaling

Kuska, Katarzyna LU ; Bettoni, Serena LU orcid ; Mohlin, Frida LU ; Chrobak, Maja LU ; Dandavate, Vaishnavi LU orcid ; Moradi, Saleh LU ; King, Ben LU orcid ; Riesbeck, Kristian LU orcid and Blom, Anna M. LU orcid (2025) In Cellular and Molecular Life Sciences 83(1).
Abstract

Complement factor C3 is one of the most abundant proteins in the bloodstream and a central part of the complement system. Upon activation, C3 facilitates bacterial recognition and clearance in the extracellular environment. Initially regarded as a serum effector component, C3 is also emerging as an intracellular protein regulating basic cellular processes. Previously, we reported that intracellular, cytosolic C3 can opsonize bacteria and impact their virulence. In this study, we show that cells lacking C3 exhibit altered gene expression that influences immune responses to infection and inflammation. We observed decreased cytokine secretion in C3-deficient cells, which was rescued by expression of non-canonical, cytosolic C3. Further... (More)

Complement factor C3 is one of the most abundant proteins in the bloodstream and a central part of the complement system. Upon activation, C3 facilitates bacterial recognition and clearance in the extracellular environment. Initially regarded as a serum effector component, C3 is also emerging as an intracellular protein regulating basic cellular processes. Previously, we reported that intracellular, cytosolic C3 can opsonize bacteria and impact their virulence. In this study, we show that cells lacking C3 exhibit altered gene expression that influences immune responses to infection and inflammation. We observed decreased cytokine secretion in C3-deficient cells, which was rescued by expression of non-canonical, cytosolic C3. Further investigation revealed that C3 deficiency impairs signal transduction within the NF-κB signaling pathway, which is attributed to decreased expression of Toll-like receptors. This effect is reversed in cells expressing cytosolic C3, where receptor expression and pathway activation are restored. Therefore, we propose a novel role of intracellular, cytosolic C3 in shaping immune responses by modulating the expression of receptors critical to pathogen recognition.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Complement component C3, Cytokines, Inflammation, Intracellular complement, Toll-like receptors
in
Cellular and Molecular Life Sciences
volume
83
issue
1
article number
1
publisher
Birkhäuser
external identifiers
  • pmid:41441980
  • scopus:105025739848
ISSN
1420-682X
DOI
10.1007/s00018-025-05975-4
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
bad9d527-ce6c-4eff-953e-30684ecd5487
date added to LUP
2026-03-10 13:08:39
date last changed
2026-08-27 14:54:34
@article{bad9d527-ce6c-4eff-953e-30684ecd5487,
  abstract     = {{<p>Complement factor C3 is one of the most abundant proteins in the bloodstream and a central part of the complement system. Upon activation, C3 facilitates bacterial recognition and clearance in the extracellular environment. Initially regarded as a serum effector component, C3 is also emerging as an intracellular protein regulating basic cellular processes. Previously, we reported that intracellular, cytosolic C3 can opsonize bacteria and impact their virulence. In this study, we show that cells lacking C3 exhibit altered gene expression that influences immune responses to infection and inflammation. We observed decreased cytokine secretion in C3-deficient cells, which was rescued by expression of non-canonical, cytosolic C3. Further investigation revealed that C3 deficiency impairs signal transduction within the NF-κB signaling pathway, which is attributed to decreased expression of Toll-like receptors. This effect is reversed in cells expressing cytosolic C3, where receptor expression and pathway activation are restored. Therefore, we propose a novel role of intracellular, cytosolic C3 in shaping immune responses by modulating the expression of receptors critical to pathogen recognition.</p>}},
  author       = {{Kuska, Katarzyna and Bettoni, Serena and Mohlin, Frida and Chrobak, Maja and Dandavate, Vaishnavi and Moradi, Saleh and King, Ben and Riesbeck, Kristian and Blom, Anna M.}},
  issn         = {{1420-682X}},
  keywords     = {{Complement component C3; Cytokines; Inflammation; Intracellular complement; Toll-like receptors}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Birkhäuser}},
  series       = {{Cellular and Molecular Life Sciences}},
  title        = {{Intracellular C3 regulates the immune response to infection via NF-κB signaling}},
  url          = {{http://dx.doi.org/10.1007/s00018-025-05975-4}},
  doi          = {{10.1007/s00018-025-05975-4}},
  volume       = {{83}},
  year         = {{2025}},
}