Biology subjects

Dangeard, A.-S.

Publications and source records attributed to Dangeard, A.-S..

3 recordsLinked to original sources

bioRxiv2026

A cilia-dependent inflammatory programme links bacterial detection to kidney disease

The primary cilium is a microtubule-based sensory organelle projecting from the plasma membrane of most mammalian cells. Genetic defects in ciliary components cause chronic kidney disease (CKD) characterized by heightened production of inflammatory and fibrogenic mediators by tubular epithelial cells. Yet, whether this reflects a physiological role of the primary cilium remains unknown. Here, we show that primary cilia on kidney tubular cells bind uropathogenic Escherichia coli and, in response to bacterial components, initiate a fibro-inflammatory program reminiscent of CKD. Integrating single-cell transcriptomics with conditional mouse models, we observed that epithelial cilia orchestrate a similar fibro-inflammatory response in the absence of infection during CKD. This convergence reveals a shared cilia-dependent signalling axis governing both host-pathogen responses and CKD progression. Mechanistically, cilia ablation selectively impairs tubular responses to ADP-heptose, a pathogen-associated molecular pattern that activates NF-{kappa}B via the cytosolic innate immune receptor ALPK1. In human kidney organoids, ADP-heptose induces robust fibro-inflammation, and genetic or pharmacological inhibition of ALPK1 attenuates this response in a rodent CKD model. Together, these findings identify primary cilia as central orchestrators of a fibro-inflammatory program linking pathogen detection to kidney disease progression.

physiology↗

bioRxiv2023

In vitro ALPK1 kinase assay reveals new insights into ADP-heptose sensing pathway and kinase activity of disease-associated ALPK1 mutants

Alpha-protein kinase 1 (ALPK1) is a pathogen recognition receptor that detects ADP-heptose (ADPH), a lipopolysaccharide biosynthesis intermediate, recently described as a pathogen-associated molecular pattern in Gram-negative bacteria. ADPH binding to ALPK1 activates its kinase domain and triggers TIFA phosphorylation on threonine 9. This leads to the assembly of large TIFA oligomers called TIFAsomes, activation of NF-{kappa}B and pro-inflammatory gene expression. Furthermore, mutations in ALPK1 are associated with inflammatory syndromes and cancers. While this kinase is of growing medical interest, only few tools are available to characterize its activity. Here, we describe a versatile non-radioactive ALPK1 in vitro kinase assay based on protein thiophosphorylation. We confirm that ALPK1 phosphorylates TIFA T9 and show that T2, T12 and T19 are also weakly phosphorylated by ALPK1. Interestingly, we find that ALPK1 itself is phosphorylated in response to ADPH recognition during Shigella flexneri and Helicobacter pylori infection and that disease-associated ALPK1 mutants exhibit altered kinase activity. In particular, T237M and V1092A mutations associated with ROSAH syndrome and spiradenoma/spiradenocarcinoma respectively, exhibit enhanced ADPH-induced kinase activity and constitutive assembly of TIFAsomes. Altogether, this study provides new insights into the ADPH sensing pathway and a new tool for measuring the activity of ALPK1.

immunology↗

bioRxiv2018

ADP-heptose is a pathogen-associated molecular pattern of Shigella flexneri infection

During an infection, the detection of pathogens is mediated through interactions between pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors. {beta}-Heptose 1,7-bisphosphate ({beta}HBP), a metabolite of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a PAMP of gram-negative bacteria. It was reported that {beta}HBP sensing leads within minutes to oligomerization of the protein TIFA, a mechanism controlling NF-{kappa}B activation and pro-inflammatory gene expression. Here, we compared the ability of chemically synthesized {beta}HBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. In contrast to lysate, we found that {beta}HBP fails to trigger rapid oligomerization of TIFA. {beta}HBP only induces delayed signaling, suggesting that it has to be processed intracellularly to induce inflammation. By dissecting the LPS biosynthesis pathway with deletion mutants and functional complementation experiments, we show that ADP-D-glycero-{beta}-D-manno-heptose and ADP-L-glycero-{beta}-D-manno-heptose are the bacterial metabolites responsible for rapid TIFA oligomerization, and that they strongly induce interleukin-8 expression during S. flexneri infection. Altogether, our results rule out a major role of {beta}HBP in S. flexneri infection and identify ADP-heptose as a new PAMP.

immunology↗