LRBA balances antigen presentation and T-cell responses by facilitating autophagy through the binding to PIK3R4 and FYCO1

Abstract

AbstractPatients with lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency have an exacerbated T-cell activation and a defective B-cell response. Previously, we suggested reduced autophagy as the biological cause of the aberrant humoral response; however, the exact molecular mechanism of LRBA in autophagy and its impact on T-cell responses remain unknown. We screened for LRBA-interacting proteins, finding that LRBA interacts with the phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and with the FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1). Interestingly, both proteins play essential roles at different stages of autophagy. Specifically, PIK3R4 facilitates the production of phosphatidylinositol-3 phosphate (PI(3)P) required for the recruitment of PI(3)P-binding adaptor proteins allowing autophagosome formation and autophagosome-lysosome fusion, whereas FYCO1 allows autophagosome movement. LRBA-KO cells showed an impaired production of PI(3)P, a delayed autophagosome-lysosome fusion, an accumulation of abnormal autophagosomes and an atypical lysosomal positioning. These observations explain the decreased cargo material degradation and the overall defective autophagy flux in LRBA-KO cells. Abnormal autophagosomes in LRBA-KO cells are associated with prolonged antigen presentation to T cells, resulting in a higher production of proinflammatory cytokines, as autophagy is a major intracellular degradation system for major histocompatibility class II complex (MHCII) loading. Taken together, our data suggest that i) LRBA forms different protein complexes serving at different stages of autophagy, and ii) loss of LRBA impacts the targeting of cytosolic antigens for autophagy degradation, enhancing antigen presentation. The latter could contribute to the exacerbated T-cell immune dysregulation observed in LRBA-deficient patients.Key pointsLRBA is required for the different steps of autophagy from autophagosome formation to cargo degradation through the interaction with PIK3R4 and FYCO1.Loss of LRBA enhances T-cell driven proinflammatory response as a consequence of increased antigen presentation.