Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation

Affiliation
Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, Germany
Di Sanzo, Simone;
GND
1110771894
ORCID
0000-0001-9611-7841
Affiliation
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
Spengler, Katrin;
GND
1316257517
ORCID
0000-0001-8129-4159
Affiliation
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
Leheis, Anja;
ORCID
0000-0001-9291-7294
Affiliation
Proteomics Science Technology Platform, The Francis Crick Institute, London, UK
Kirkpatrick, Joanna M.;
GND
1316258637
ORCID
0000-0002-2075-5940
Affiliation
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
Rändler, Theresa L.;
Affiliation
Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
Baldensperger, Tim;
ORCID
0000-0003-0251-9490
Affiliation
Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, Germany
Dau, Therese;
ORCID
0000-0003-3109-8330
Affiliation
Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
Henning, Christian;
ORCID
0000-0002-0924-8518
Affiliation
Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy
Parca, Luca;
Affiliation
Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, Germany
Marx, Christian;
GND
1216659737
Affiliation
Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, Jena, Germany
Wang, Zhao-Qi;
Affiliation
Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
Glomb, Marcus A.;
ORCID
0000-0002-3046-0871
Affiliation
Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, Germany
Ori, Alessandro;
GND
1153831414
ORCID
0000-0002-1703-1925
Affiliation
Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
Heller, Regine

Abstract Posttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devise a proteomic strategy to identify sites of carboxymethyllysine modification, one of the most abundant advanced glycation end products. We identify over 1000 sites of protein carboxymethylation in mouse and primary human cells treated with the glycating agent glyoxal. By using quantitative proteomics, we find that protein glycation triggers a proteotoxic response and indirectly affects the protein degradation machinery. In primary endothelial cells, we show that glyoxal induces cell cycle perturbation and that carboxymethyllysine modification reduces acetylation of tubulins and impairs microtubule dynamics. Our data demonstrate the relevance of carboxymethyllysine modification for cellular function and pinpoint specific protein networks that might become compromised during aging. Accumulation of advanced glycation end products such as carboxymethyllysine (CML) has been associated with aging but their molecular roles are largely unclear. Here, the authors use proteomics to identify CML sites and show that CML formation affects protein homeostasis and cell proliferation.

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