Biology subjects

Pelle, O.

Publications and source records attributed to Pelle, O..

3 recordsLinked to original sources

bioRxiv2025

NAP1 switches from an activator to a limiter of interferon induction by trapping TBK1 in condensates

TBK1 kinase is a central regulator of type I IFN production. Upon activation of the IFN-{beta} induction pathway, TBK1-adaptor proteins (NAP1, SINTBAD, TANK) form condensates with liquid properties. We showed that NAP1 condensates concentrate TBK1. Using NAP1KO cell lines, we discovered that NAP1 exerts a dual effect on TBK1 activity. Initially, NAP1 binds TBK1 and increases its activity, which enhances the activation of the IFN pathway. Then, phosphorylation of NAP1 by TBK1 induces the formation of NAP1 condensates. These condensates concentrate TBK1 and PP2A, a phosphatase known to dephosphorylate and consequently deactivate TBK1, thus limiting IFN induction. Additionally, in patients with lupus or interferonopathies, we identified NAP1 variants, unable to form condensates upon cell exposure to danger signals, which can only activate TBK1 without limiting its activity. This study reveals an original mode of regulating a signaling pathway by formation of condensates and provides a molecular explanation for certain interferonopathies.

immunology↗

bioRxiv2020

Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

Systemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-{kappa}B consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFN-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets. SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFN-consensus sequences.

immunology↗

bioRxiv2020

FGFR3 is a positive regulator of osteoblast expansion and differentiation during zebrafish skull vault development

Gain- or loss-of-function mutations in fibroblast growth factor receptor 3 (FGFR3) result in cranial vault defects - highlighting the proteins role in membranous ossification. Zebrafish express high levels of fgfr3 during skull development; in order to study FGFR3s role in cranial vault development, we generated the first fgfr3 loss-of-function zebrafish (fgfr3lof/lof). The mutant fish exhibited major changes in the craniofacial skeleton, with a lack of sutures, abnormal frontal and parietal bones, and the presence of ectopic bones. Integrated analyses (in vivo imaging, and single-cell RNA sequencing of the osteoblast lineage) of zebrafish fgfr3lof/lof revealed a delay in osteoblast expansion and differentiation, together with changes in the extracellular matrix. These findings demonstrate that fgfr3 is a positive regulator of osteogenesis. We hypothesize that changes in the extracellular matrix within growing bone impair cell-cell communication, mineralization, and new osteoblast recruitment.

developmental biology↗