Ph.D., National Yang-Ming University (National Yang Ming Chiao Tung University), Taiwan, Microbiology and Immunology (2019)
M.S., National Cheng Kung University, Taiwan, Medical Laboratory Science and Biotechnology (2010)
B.S., Ming Chuan University, Taiwan, Biotechnology (2008)
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