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Arf1-dependent LRBA recruitment to Rab4 endosomes is required for endolysosome homeostasis

ABSTRACT: Deleterious mutations in the LRBA (Lipopolysaccharide Responsive Beige-like Anchor protein) gene cause severe childhood immune dysregulation. The clinical manifestations of LRBA deficiency syndrome are highly variable. Thus, the complexity of the symptoms involving multiple organs and the broad range of unpredictable clinical manifestations complicate the choice of therapeutic interventions. Although LRBA has been linked to Rab11-dependent trafficking of the immune checkpoint protein CTLA-4, its precise cellular role remains elusive. We show that LRBA, however, only slightly colocalize with Rab11. Instead, LRBA is recruited by members of the small GTPase Arf protein family to the TGN and to Rab4+ endosomes, where it controls intracellular traffic. In patient-derived fibroblasts, loss of LRBA led to defects in the endosomal pathway yielding the accumulation of enlarged endolysosomes and lysosome secretion. Thus, LRBA appears to regulate flow through the endosomal system on Rab4+ endosomes. Our data strongly suggest functions of LRBA beyond CTLA-4 trafficking and provide a conceptual framework to develop new therapies for LRBA deficiency.

INSTRUMENT(S): timsTOF Ultra, Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Alexander Schmidt

PROVIDER: MSV000095230 | MassIVE | Wed Jul 03 06:50:00 BST 2024

SECONDARY ACCESSION(S): PXD053605

REPOSITORIES: MassIVE

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