Borcs6 is required for endo‐lysosomal degradation during early development

Bell, Charlotte J; Gupta, Neha; Tremblay, Kimberly D.; Mager, Jesse

doi:10.1002/mrd.23626

Cited by 3 publications

(2 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another reported function of the BORC-Arl8b complex is the regulation of vesicle fusion between late endosomes and lysosomes ( 22 , 23 ). We reasoned that by regulating lysosome fusion, BORC would be able to control the turnover of membrane proteins targeted for lysosomal degradation, including TLR7.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, mice with attenuated BORC function develop progressive axonal dystrophy and impaired motor function (42). Global KO mice of individual BORC subunits or Arl8b are not viable (22,(42)(43)(44). These animal studies give reason to predict that humans with attenuated BORC function would foremost present with neurodegenerative disorders, which, notably, frequently cooccur with autoinflammatory or autoimmune disease and often share genetic variants and pathways (45).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Disrupted degradative sorting of TLR7 is associated with human lupus

Mishra,

Schlack-Leigers,

Lim

et al. 2024

Sci. Immunol.

View full text Add to dashboard Cite

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disrupted degradative sorting of TLR7 is associated with human lupus

Mishra,

Schlack-Leigers,

Lim

et al. 2024

Sci. Immunol.

View full text Add to dashboard Cite

show abstract

Unveiling differential gene co-expression networks and its effects on levodopa-induced dyskinesia

Piedade de Souza,

Santana de Araújo,

Magalhães

et al. 2024

iScience

View full text Add to dashboard Cite

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

Mishra

Schlack-Leigers

Lim

et al. 2023

Preprint

View full text Add to dashboard Cite

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 models. Recently, mutations in TLR7 or its associated regulator UNC93B1, 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 endosomes. 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.

show abstract

Borcs6 is required for endo‐lysosomal degradation during early development

Cited by 3 publications

References 34 publications

Disrupted degradative sorting of TLR7 is associated with human lupus

Disrupted degradative sorting of TLR7 is associated with human lupus

Unveiling differential gene co-expression networks and its effects on levodopa-induced dyskinesia

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

Contact Info

Product

Resources

About