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Cited by 40Genetic and Kidney Cyst DiseasesNF-κB Signaling PathwaysCystic Fibrosis Research Advances

Ciliary proteins specify the cell inflammatory response by tuning NFκB signalling, independently of primary cilia

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Mc Fie, Megan, Koneva, Lada, Collins, Isabella, Coveney, Clarissa R., Clube, Aisling M., Chanalaris, Anastasios, Vincent, Tonia L., Bezbradica, Jelena S. +2 more·2020·Journal of Cell Science
DOI 10.1242/jcs.239871PMC PMC7358134
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Abstract

Complex inflammatory signalling cascades define the response to tissue injury but also control development and homeostasis, limiting the potential for these pathways to be targeted therapeutically. Primary cilia are subcellular regulators of cellular signalling, controlling how signalling is organized, encoded and, in some instances, driving or influencing pathogenesis. Our previous research revealed that disruption of ciliary intraflagellar transport (IFT), altered the cell response to IL-1β, supporting a putative link emerging between cilia and inflammation. Here, we show that IFT88 depletion affects specific cytokine-regulated behaviours, changing cytosolic NFκB translocation dynamics but leaving MAPK signalling unaffected. RNA-seq analysis indicates that IFT88 regulates one third of the genome-wide targets, including the pro-inflammatory genes Nos2, Il6 and Tnf. Through microscopy, we find altered NFκB dynamics are independent of assembly of a ciliary axoneme. Indeed, depletion of IFT88 inhibits inflammatory responses in the non-ciliated macrophage. We propose that ciliary proteins, including IFT88, KIF3A, TTBK2 and NPHP4, act outside of the ciliary axoneme to tune cytoplasmic NFκB signalling and specify the downstream cell response. This is thus a non-canonical function for ciliary proteins in shaping cellular inflammation. This article has an associated First Person interview with the first author of the paper.

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  • COX2 is upregulated upon IL-1β stimulation in cells in which the expression of Kif3A and TTBK2 is inhibited.

    “In contrast, COX2 was upregulated upon IL-1β stimulation in cells in which the expression of Kif3A and TTBK2, which are also essential for primary cilium formation and maintenance similar to IFT88, was inhibited (Mc Fie et al. 2020).”

    From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Mc Fie et al. 2020

  • There is a primary cilium-independent mechanism that regulates the expression of inflammatory mediators or the inflammatory signalling within cilia is intricately controlled by multiple molecules.

    “These findings suggest that there is a primary cilium-independent mechanism that regulates the expression of inflammatory mediators or that the inflammatory signalling within cilia is intricately controlled by multiple molecules (Mc Fie et al. 2020).”

    From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Mc Fie et al. 2020

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Cited by

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Authors
Mc Fie, M., Koneva, L., Collins, I., Coveney, C. R., Clube, A. M., Chanalaris, A., Vincent, T. L., Bezbradica, J. S., Sansom, S. N., & Wann, A. K. T.
Affiliations
  • Kennedy Institute of Rheumatology Research 1 , Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Medical Sciences Division , , Oxford OX3 7FY , UK
  • University of Oxford (GB)
Corresponding author
Wann, Angus K. T.
ORCID
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2020-07-01
Volume
133
Issue
13
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.239871
PMC
PMC7358134
OpenAlex
W3027212124
Cited by
40
References
3
Citations by year
2026: 7 · 2025: 5 · 2024: 9 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 4
FWCI
2.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cell Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by)
Funders
  • Kennedy Trust for Rheumatology Research (KENN 15 16 06)
  • Arthritis Research UK
  • Queen Mary University of London
  • Versus Arthritis (21546, 20887)
  • New College, University of Oxford
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
Keywords
primary cilia, IFT88, inflammation, intraflagellar transport, macrophages, KIF3A, TTBK2, NPHP4, cytokine response, IL-1β, MAPK signaling, pro-inflammatory genes, NOS2, interleukin-6, TNF-α
MeSH terms
Cilia, Flagella, Signal Transduction, NF-kappa B, Protein Transport

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