Role of the Senescence-Associated Factor Dipeptidyl Peptidase 4 in the Pathogenesis of SARS-CoV-2 Infection

• Published in: Aging and disease Vol. 15; no. 3; pp. 1398 - 1415
• Main Authors: Deinhardt-Emmer, Stefanie, Deshpande, Sharvari, Kitazawa, Koji, Herman, Allison B, Bons, Joanna, Rose, Jacob P, Kumar, Prasanna Ashok, Anerillas, Carlos, Neri, Francesco, Ciotlos, Serban, Perez, Kevin, Köse-Vogel, Nilay, Häder, Antje, Abdelmohsen, Kotb, Löffler, Bettina, Gorospe, Myriam, Desprez, Pierre-Yves, Melov, Simon, Furman, David, Schilling, Birgit, Campisi, Judith
• Format: Journal Article
• Language: English
• Published: United States JKL International 01.06.2024; JKL International LLC
• Subjects: Age factors in disease; Aged; Aging; Cells, Cultured; Cellular Senescence; COVID-19 - metabolism; COVID-19 - pathology; Dipeptidyl Peptidase 4 - genetics; Dipeptidyl Peptidase 4 - metabolism; Female; Health aspects; Humans; Lung - metabolism; Lung - pathology; Lung - virology; Male; Middle Aged; Original; Physiological aspects; Proteases; SARS-CoV-2; Zonula Occludens-1 Protein - metabolism; United States
• ISSN: 2152-5250; 2152-5250
• DOI: 10.14336/AD.2023.0812

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.