Biology subjects

Crow, Y.

Publications and source records attributed to Crow, Y..

3 recordsLinked to original sources

bioRxiv2026

Loss of MTPAP disrupts mitochondrial RNA processing causing upregulation of type I interferon signalling

Mitochondrial poly-A polymerase (MTPAP) is essential for mitochondrial mRNA (mt-mRNA) polyadenylation, a critical step in mt-mRNA maturation. Mutations in MTPAP have been reported to cause a mitochondrial cytopathy. Here, we provide evidence of enhanced type I interferon (IFN) signalling in the blood of patients carrying mutations in MTPAP. Further, deletion of MTPAP in a fibroblast cell model led to abnormalities in mitochondrial respiration and mtRNA processing, and an upregulation of type I IFN signalling. Notably, both in patients fibroblast and in MTPAP-deleted cells, we observed the accumulation of non-coding mtRNA and mitochondrial double-stranded RNA (mt-dsRNA) within enlarged mitochondrial RNA granules. Cytosolic release of mt-dsRNA led to type I IFN induction mediated primarily by the RNA sensor MDA5 and its adaptor MAVS. Our findings reveal a novel consequence of MTPAP dysfunction, highlighting how impaired mtRNA maturation can drive innate immune system activation.

cell biology↗

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↗

bioRxiv2024

Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling

The cGAS-STING pathway detects cytosolic DNA and activates a signaling cascade that results in a type I interferon (IFN) response. The endoplasmic reticulum (ER)-associated exonuclease TREX1 suppresses cGAS-STING by eliminating DNA from the cytosol. Mutations that compromise TREX1 function are linked to autoinflammatory disorders, including systemic lupus erythematosus (SLE) and Aicardi-Goutieres syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associated TREX1 mutations - particularly those outside of the core catalytic domains - remains poorly understood. Here, we characterize a recessive AGS-linked TREX1 P61Q mutation occurring within the poorly characterized polyproline helix (PPII) motif. In keeping with its position outside of the catalytic core or ER targeting motifs, neither the P61Q mutation, nor aggregate proline-to-alanine PPII mutation, disrupt TREX1 exonuclease activity, subcellular localization, or cGAS-STING regulation in overexpression systems. Introducing targeted mutations into the endogenous TREX1 locus revealed that PPII mutations destabilize the protein, resulting in impaired exonuclease activity and unrestrained cGAS-STING activation. Overall, these results demonstrate that TREX1 PPII mutations, including P61Q, impair proper immune regulation and lead to autoimmune disease through TREX1 destabilization.

genetics↗