PXD040042

PXD040042 is an original dataset announced via ProteomeXchange.

Title	Proteome analysis of WT and Borcs5 phagosomes from Raw264.7 macrophages
Description	Hyperactive TLR7 signaling has long been appreciated as a driver of autoimmune disease in mouse models by breaking tolerance to self-nucleic acids1-5. Recently, the first monogenic mutations within TLR7 or its associated regulator Unc93b16,7 have been identified as causative agents of human lupus. The unifying feature of these mutations is TLR7 gain-of-function resulting from increased ligand binding. TLR7 is an intracellular transmembrane receptor, localized to late endosomes, that senses RNA breakdown products within these hydrolytic compartments8,9. Hence, its function depends on a complex interplay between specialized organelles, transport mechanisms and membrane interactions. 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 can result in TLR7 gain-of-function and lupus disease in humans. Mechanistically, the late endosomal protein complex BORC-Arl8b controls TLR7 protein levels by mediating the receptor's final sorting step towards lysosomal degradation. A direct interaction between Arl8b and Unc93b1 is required to regulate the turnover of TLR7. We identified an amino acid insertion in Unc93b1 in a patient with childhood-onset lupus, which results in loss of interaction with the BORC-Arl8b complex and an accumulation of functional TLR7. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease. Disrupting the proper progression of TLR7 through its endocytic life cycle is sufficient to break immunological tolerance to nucleic acids. Our work expands the repertoire of cellular mechanisms important to restrict pathological TLR7 activity. Identifying and stratifying lupus patients based on a TLR7-driven pathology opens the way for precision medicine specifically targeting TLR7.
HostingRepository	PRIDE
AnnounceDate	2023-11-22
AnnouncementXML	Submission_2023-11-22_04:04:32.351.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Meierhofer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF SCP

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-10 08:16:51	ID requested
⏵ 1	2023-11-22 04:04:32	announced

Dataset with its publication pending

submitter keyword: Borcs5, phagosomes

Olivia Majer
contact affiliation	Max Planck Institute for Infection Biology, Berlin, Germany
contact email	majer@mpiib-berlin.mpg.de
lab head
David Meierhofer
contact affiliation	Mass Spectrometry Facility MPIMG
contact email	meierhof@molgen.mpg.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/11/PXD040042

PRIDE project URI

• PRIDE
  1. PXD040042
     1. Label: PRIDE project
     2. Name: Proteome analysis of WT and Borcs5 phagosomes from Raw264.7 macrophages