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

J Cell Biol. 2024 Nov 4;223(11):e202401167. doi: 10.1083/jcb.202401167. Epub 2024 Sep 26.

Abstract

Deleterious mutations in the lipopolysaccharide responsive beige-like anchor protein (LRBA) gene cause severe childhood immune dysregulation. The complexity of the symptoms involving multiple organs and the broad range of unpredictable clinical manifestations of LRBA deficiency 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 colocalizes 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 promoting 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.

MeSH terms

  • ADP-Ribosylation Factor 1
  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism
  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Endosomes* / metabolism
  • Fibroblasts / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Homeostasis*
  • Humans
  • Lysosomes* / metabolism
  • Protein Transport
  • rab GTP-Binding Proteins* / genetics
  • rab GTP-Binding Proteins* / metabolism
  • rab4 GTP-Binding Proteins* / genetics
  • rab4 GTP-Binding Proteins* / metabolism
  • trans-Golgi Network / metabolism

Substances

  • rab4 GTP-Binding Proteins
  • LRBA protein, human
  • rab GTP-Binding Proteins
  • Adaptor Proteins, Signal Transducing
  • ARF1 protein, human
  • ADP-Ribosylation Factors
  • rab11 protein
  • ADP-Ribosylation Factor 1