Biology subjects

Majer, O.

Publications and source records attributed to Majer, O..

4 recordsLinked to original sources

bioRxiv2025

Microbial Priming Enhances TLR7-Driven Myddosome Assembly Dynamics

Cells can modify their future behavior based on prior exposures, a phenomenon known as cellular adaptation. In innate immunity, such adaptive responses are critical for fine-tuning host defense, enabling trained immunity or tolerance. These states have been largely attributed to long-lasting epigenetic or metabolic reprogramming. Whether prior microbial encounters can rapidly lower receptor signaling thresholds to selectively enhance responsiveness of individual innate immune receptors remains unknown. Here, we identify a previously unrecognized, non-genetic form of cellular adaptation. We show that TLR4 activation by LPS, while inducing classical endotoxin tolerance, simultaneously primes macrophages for enhanced responses to subsequent activation of the RNA sensor TLR7. Because TLR4 and TLR7 use the same signaling machinery, this indicates that they are selectively reprogrammed in this process. TLR7 training requires type I interferons and is marked by a strong increase in Myddosome assemblies at endosomal membranes, without changes in TLR7 abundance or ligand uptake. These findings reveal that innate immune training can be rapidly encoded at the level of receptor-proximal signaling, linking microbial priming to enhanced nucleic acid immunity and potentially to TLR7-driven autoimmunity in genetically predisposed individuals. Short summaryLPS priming drives receptor-proximal immune adaptation in macrophages, inducing classical TLR4 endotoxin tolerance while simultaneously sensitizing the RNA sensor TLR7 by enhancing Myddosome nucleation at endosomal membranes. This compartment- and receptor specific reprogramming may link prior infection history to elevated risk of TLR7-driven autoimmunity.

cell biology↗

bioRxiv2023

Endosome dysfunction leads to gain-of-function TLR7 and human lupus

Hyperactive Toll-like receptor (TLR) 7 signaling has long been appreciated as a driver of autoimmune disease by breaking tolerance to self-nucleic acids in mouse models1-5. Recently, mutations in TLR7 or its associated regulator UNC93B16, 7, were identified as monogenic causes of human lupus; the unifying feature of these mutations being TLR7 gain-of-function. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes8, 9. Hence, its function depends on intricate transport mechanisms and membrane interactions within the endomembrane network. Whether perturbations of any of these endosome-related processes can give rise to TLR7 gain-of-function and facilitate self-reactivity has not been investigated. Here, we show that a dysregulated endosomal compartment leads to unrestricted TLR7 signaling and human lupus. The late endosomal BLOC-1-related protein complex (BORC) together with the small Arf1-like GTPase Arl8b controls TLR7 protein levels, and a direct interaction between Arl8b and Unc93b1 is required to regulate TLR7 turnover. We identified an amino acid insertion in UNC93B1 in a patient with childhood-onset lupus, which reduces the interaction with the BORC-Arl8b complex and leads to endosomal TLR7 accumulation. Therefore, a failure to control the proper progression of TLR7 through its endocytic life cycle is sufficient to break immunological tolerance to nucleic acids in humans. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease. As the cellular mechanisms restricting TLR7 signaling can be manifold, identifying and stratifying lupus patients based on a TLR7-driven pathogenesis could be a viable strategy towards a targeted therapy.

immunology↗

bioRxiv2018

Unc93b1 recruits Syntenin-1 to dampen TLR7 signaling and prevent autoimmunity

Recognition of nucleic acids enables detection of diverse pathogens by a limited number of innate immune receptors but also exposes the host to potential autoimmunity. At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self RNA or DNA, respectively. Despite the structural and functional similarities between these receptors, their contribution to autoimmune diseases such as SLE can be quite different. However, mechanisms of negative regulation that differentiate between TLR7 and TLR9 have not been described. Here we report a new function for the TLR trafficking chaperone Unc93b1 that specifically limits TLR7 signaling and prevents TLR7-dependent autoimmunity. Unc93b1 is known to traffic TLRs from the endoplasmic reticulum to endosomes, but this new regulatory function does not affect TLR7 localization. Instead, Unc93b1 recruits Syntenin-1, which inhibits TLR7, but not TLR9, signaling. Syntenin-1 binding requires phosphorylation of two serine residues on Unc93b1, providing a mechanism for dynamic regulation of the activation threshold of TLR7. Disruption of the Unc93b1/Syntenin-1 interaction in mice results in TLR7-dependent autoimmunity. Thus, Unc93b1 not only enables proper trafficking of nucleic acid sensing TLRs but also sets the activation threshold of these potentially self-reactive receptors.

immunology↗

bioRxiv2018

An essential checkpoint for TLR9 signaling is release from 1 Unc93b1 in endosomes

AbstractNucleic acid-sensing Toll-like receptors (TLRs) are subject to complex regulation to facilitate recognition of microbial DNA and RNA while limiting recognition of self-nucleic acids1. Failure to properly regulate nucleic acid-sensing TLRs can lead to autoimmune and autoinflammatory disease2-6. Intracellular localization of these receptors is thought to be critical for self vs. non-self discrimination7, yet the molecular mechanisms that reinforce compartmentalized activation of intracellular TLRs remain poorly understood. Here we describe a new mechanism that prevents TLR9 activation from locations other than endosomes. This control is achieved through the regulated release of TLR9 from its trafficking chaperone Unc93b1, which only occurs within endosomes and is required for ligand binding and signal transduction. Mutations in Unc93b1 that increase affinity for TLR9 impair release and result in defective signaling. The release is specific to TLR9, as TLR7 does not dissociate from Unc93b1 in endosomes. This work defines a novel checkpoint that reinforces self vs. non-self discrimination by TLR9 and provides a mechanism by which TLR9 and TLR7 activation can be distinctly regulated.

immunology↗