1. Role of the Senescence-Associated Factor Dipeptidyl Peptidase 4 in the Pathogenesis of SARS-CoV-2 Infection.
- Author
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Deinhardt-Emmer S, Deshpande S, Kitazawa K, Herman AB, Bons J, Rose JP, Kumar PA, Anerillas C, Neri F, Ciotlos S, Perez K, Köse-Vogel N, Häder A, Abdelmohsen K, Löffler B, Gorospe M, Desprez PY, Melov S, Furman D, Schilling B, and Campisi J
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Cells, Cultured, Cellular Senescence, Lung metabolism, Lung virology, Lung pathology, SARS-CoV-2, Zonula Occludens-1 Protein metabolism, COVID-19 metabolism, COVID-19 pathology, Dipeptidyl Peptidase 4 metabolism, Dipeptidyl Peptidase 4 genetics
- Abstract
During cellular senescence, persistent growth arrest and changes in protein expression programs are accompanied by a senescence-associated secretory phenotype (SASP). In this study, we detected the upregulation of the SASP-related protein dipeptidyl peptidase 4 (DDP4) in human primary lung cells rendered senescent by exposure to ionizing radiation. DPP4 is an exopeptidase that plays a crucial role in the cleavage of various proteins, resulting in the loss of N-terminal dipeptides and proinflammatory effects. Interestingly, our data revealed an association between severe coronavirus disease 2019 (COVID-19) and DDP4, namely that DPP4 levels increased in the plasma of patients with COVID-19 and were correlated with age and disease progression. Although we could not determine the direct effect of DDP4 on viral replication, mechanistic studies in cell culture revealed a negative impact on the expression of the tight junction protein zonula occludens-1 (ZO-1), which contributes to epithelial barrier function. Mass spectrometry analysis indicated that DPP4 overexpressing cells exhibited a decrease in ZO-1 and increased expression of pro-inflammatory cytokines and chemokines. By investigating the effect of DPP4 on the barrier function of human primary cells, we detected an increase in ZO-1 using DPP4 inhibitors. These results provide an important contribution to our understanding of DPP4 in the context of senescence, suggesting that DPP4 plays a major role as part of the SASP. Our results provide evidence that cellular senescence, a hallmark of aging, has an important impact on respiratory infections.
- Published
- 2024
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