Chaitan Khosla, Postdoctoral Faculty Sponsor
LRP-1 links post-translational modifications to efficient presentation of celiac disease-specific Tcell antigens.
Cell chemical biology
Celiac disease (CeD) is an autoimmune disorder in which gluten-derived antigens trigger inflammation. Antigenic peptides must undergo site-specific deamidation to be presentable to CD4+ Tcells in an HLA-DQ2 or -DQ8 restricted manner. While the biochemical basis for this post-translational modification is understood, its localization in the patient's intestine remains unknown. Here, we describe a mechanism by which gluten peptides undergo deamidation and concentration in the lysosomes of antigen-presenting cells, explaining how the concentration of gluten peptides necessary to elicit an inflammatory response in CeD patients is achieved. A ternary complex forms between a gluten peptide, transglutaminase-2 (TG2), and ubiquitous plasma protein alpha2-macroglobulin, and is endocytosed by LRP-1. The covalent TG2-peptide adduct undergoes endolysosomal decoupling, yielding the expected deamidated epitope. Our findings invoke a pathogenic role for dendritic cells and/or macrophages in CeD and implicate TG2 in the lysosomal clearance of unwanted self and foreign extracellular proteins.
View details for DOI 10.1016/j.chembiol.2022.12.002
View details for PubMedID 36608691