biostudies-literatureSindram EDeutsche Forschungsgemeinschaft (DFG)Bundesministerium für Bildung und ForschungCenter for Integrative Biological Signalling StudiesDeutsche ForschungsgemeinschaftEuropean Research CouncilEuropäische Konföderation der Oberrheinischen Universitäten (EUCOR)Europäische Konföderation der Oberrheinischen UniversitätenFritz Thyssen StiftungHans A. Krebs, Faculty of Medicine, University Medical Center FreiburgBundesministerium für Bildung und Forschung (BMBF)Fritz Thyssen Stiftung (Fritz Thyssen Foundation)Medical Faculty, University of Freiburg4040-4071https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373796biostudies-literatureUnknown26(16)Reduced autophagy is associated with the aberrant humoral response observed in lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency; however, the molecular mechanisms and their impact on T-cell responses remain poorly understood. We identify two novel LRBA interactors, phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1), which each play key roles in autophagy. PIK3R4 facilitates the production of phosphatidylinositol-3 phosphate (PI(3)P) that promotes autophagosome formation and autophagosome-lysosome fusion, whereas FYCO1 supports autophagosome movement. LRBA-knockout (KO) cells show impaired PI(3)P production, reduced autophagosome-lysosome fusion, accumulation of enlarged autophagosomes, and decreased cEMBO reportsLRBA deficiency impairs autophagy and contributes to enhanced antigen presentation and T-cell dysregulation.PMC1237379610.18.1.039MNIFB/CCI: 01E0130301GM1517CACTIv403222702 - SFB 1381GR1617/8-1IMPATH-SFB SFB1160/2Project Number 2021/B3-FolE-med SysINFLAME: 012X1306FCIBSS - EXC-2189- Project ID 390939984769065Project Number 450392965Project-IDs 450216812,409673687,SFB 1381 (Project ID 403222702),SFB 1177 (Project ID 259130777)CIBSS-EXC-2189 Project ID 390939984Proietti MMishra PGrimbacher BSindram EKraft CRambold ARoussa EDeau MCRuf SLigeon LANestel SThedieck KGamez-Diaz LSanchez-Martin PGunther SJung SMunz CfalseLRBA deficiency impairs autophagy and contributes to enhanced antigen presentation and T-cell dysregulation.Reduced autophagy is associated with the aberrant humoral response observed in lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency; however, the molecular mechanisms and their impact on T-cell responses remain poorly understood. We identify two novel LRBA interactors, phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1), which each play key roles in autophagy. PIK3R4 facilitates the production of phosphatidylinositol-3 phosphate (PI(3)P) that promotes autophagosome formation and autophagosome-lysosome fusion, whereas FYCO1 supports autophagosome movement. LRBA-knockout (KO) cells show impaired PI(3)P production, reduced autophagosome-lysosome fusion, accumulation of enlarged autophagosomes, and decreased c2025-01-01T00:00:00Z2025 Aug2026-05-08T10:46:36.413Z2026-04-07T23:47:27.644ZS-EPMC123737964055095410.1038/s44319-025-00504-7