LRP-1 links post-translational modifications to efficient presentation of celiac disease-specific T cell antigens

Cell Chem Biol. 2023 Jan 19;30(1):55-68.e10. doi: 10.1016/j.chembiol.2022.12.002. Epub 2023 Jan 5.


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+ T cells 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 α2-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.

Keywords: LRP-1; MHC-II; antigen presentation; celiac disease; transglutaminase-2; α(2)-macroglobulin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Celiac Disease* / metabolism
  • Celiac Disease* / pathology
  • Glutens / metabolism
  • Humans
  • Peptides / metabolism
  • Protein Processing, Post-Translational
  • T-Lymphocytes


  • Glutens
  • Peptides
  • LRP1 protein, human