Discovery and engineering the TG2/LRP-1 pathway for lysosomal delivery of molecular cargo : implications for celiac disease
Abstract/Contents
- Abstract
- Celiac disease (CeD) is a systemic, inflammatory immune disorder that primarily affects the small intestine. It is triggered by the consumption of dietary gluten, derived from wheat, barley, or rye in certain genetically susceptible individuals. Gluten peptides are rendered highly antigenic to CeD patients through deamidation at certain epitopes by transglutaminase-2 (TG2), a widely expressed and multifunctional enzyme. Over 95% of all CeD patients express HLA-DQ2, and a vast majority of the remaining population express HLA-DQ8, and in these individuals the deamidated peptides tightly bind MHC-II on the surface of antigen presenting cells (APCs) and are then presented to gluten-specific CD4+ T cells. TG2 activity is necessary for peptide deamidation as demonstrated by restoration of a healthy phenotype upon TG2 inhibition in a mouse model of CeD. Thus, understanding the activity and localization of TG2 could help understand the mechanisms underlying CeD, and how APCs take up TG2 and gluten peptides leading to the hallmark T cell response. In my dissertation I discuss a new pathway for gluten antigen uptake and presentation in celiac disease, and how this pathway can be utilized for therapeutic applications. This pathway relies on the protein-protein interactions between three different widely expressed proteins, TG2, α2-macroglobulin and LRP-1. The complex that forms between TG2 and its gluten substrate is recognized by α2- macroglobulin, an abundant plasma protein, which leads to a conformational change. This conformation is recognized by its canonical cell surface receptor, LRP-1, triggering an endocytic event eventually delivering the cargo to the lysosome. In HLA-DQ2 expressing cells the deamidated gluten peptide released in the lysosome binds to MHC-II and is presented on the cell surface. The antigens presented on the cell surface through this pathway efficiently activate gluten-reactive T cells. Finally, this pathway can be hijacked to induce the lysosomal degradation of proteins of interest. A ligand to the protein of interest is conjugated to a gluten peptide, allowing for the entire complex to be endocytosed in an LRP-1 dependent manner. The molecular cargo, including the protein of interest is degraded, and LRP-1 is recycled to the cell surface. This approach could be used to target therapeutically relevant proteins without needing to inhibit them, in a manner analogous to LYTACs, but using only small molecules. Overall, this work offers insight into the molecular mechanisms behind antigen presentation in CeD, and how this knowledge can be used to design novel therapeutics for CeD and other diseases.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2024; ©2024 |
| Publication date | 2024; 2024 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Loppinet, Elise Marie Nicolette |
|---|---|
| Degree supervisor | Khosla, Chaitan, 1964- |
| Thesis advisor | Khosla, Chaitan, 1964- |
| Thesis advisor | Abu-Remaileh, Monther |
| Thesis advisor | Swartz, James R |
| Degree committee member | Abu-Remaileh, Monther |
| Degree committee member | Swartz, James R |
| Associated with | Stanford University, School of Engineering |
| Associated with | Stanford University, Department of Chemical Engineering |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Elise Loppinet. |
|---|---|
| Note | Submitted to the Department of Chemical Engineering. |
| Thesis | Thesis Ph.D. Stanford University 2024. |
| Location | https://purl.stanford.edu/mz926sf6319 |
Access conditions
- Copyright
- © 2024 by Elise Marie Nicolette Loppinet
- License
- This work is licensed under a Creative Commons Attribution 3.0 Unported license (CC BY).
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