Posttranslationally modified self-peptides promote hypertension in mouse models
Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G. Harrison
Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G. Harrison
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Research Article Cardiology Immunology

Posttranslationally modified self-peptides promote hypertension in mouse models

Abstract

Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain–containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.

Authors

Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G. Harrison

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Figure 2

A computational modeling pipeline predicts IsoLG-adducted peptides presented by H-2Db.

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A computational modeling pipeline predicts IsoLG-adducted peptides prese...
(A and B) Rosetta scores are more favorable (more negative) for peptides known to bind to H-2Kb (A) and H-2Db (B) when compared with known nonbinders. ***P < 0.001 by Mann-Whitney test. (C) When lysine-containing peptides are adducted with IsoLG in silico, Rosetta predicts smaller (more favorable) score changes if those peptides are bound to H-2Db compared with H-2Kb (solid bars = mean, dashed line = median, box boundaries = interquartile range, error bars ± min/max values). *P < 0.05 by Mann-Whitney test. (D) Rosetta score changes after in silico IsoLG adduction for all nonanchoring residues in lysine-containing H-2Db–bound epitopes predict residue sites 4, 6, and 7 as energetically favorable positions (positions at which multiple peptides modeled have no score increase after adduction. Black bars indicate mean Δ Rosetta score). (E) These residues correspond to areas recognized by T cell receptors interacting with H-2Db epitopes. (F) Strategy for identifying a library of peptide candidates to screen in vitro and in vivo.