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

Autor: Deinhardt-Emmer S; Buck Institute for Research on Aging, Novato, CA 94945, USA.; Institute of Medical Microbiology, Jena University Hospital, Germany., Deshpande S; Buck Institute for Research on Aging, Novato, CA 94945, USA., Kitazawa K; Buck Institute for Research on Aging, Novato, CA 94945, USA., Herman AB; Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA., Bons J; Buck Institute for Research on Aging, Novato, CA 94945, USA., Rose JP; Buck Institute for Research on Aging, Novato, CA 94945, USA., Kumar PA; Buck Institute for Research on Aging, Novato, CA 94945, USA., Anerillas C; Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA., Neri F; Buck Institute for Research on Aging, Novato, CA 94945, USA., Ciotlos S; Buck Institute for Research on Aging, Novato, CA 94945, USA., Perez K; Buck Institute for Research on Aging, Novato, CA 94945, USA., Köse-Vogel N; Institute of Medical Microbiology, Jena University Hospital, Germany., Häder A; Institute of Medical Microbiology, Jena University Hospital, Germany., Abdelmohsen K; Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA., Löffler B; Institute of Medical Microbiology, Jena University Hospital, Germany., Gorospe M; Laboratory of Genetics and Genomics, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA., Desprez PY; Buck Institute for Research on Aging, Novato, CA 94945, USA., Melov S; Buck Institute for Research on Aging, Novato, CA 94945, USA., Furman D; Stanford 1000 Immunomes Project, Stanford University School of Medicine, Stanford, CA 94305, USA.; Buck Artificial Intelligence Platform, Buck Institute for Research on Aging, Novato, CA 94945, USA., Schilling B; Buck Institute for Research on Aging, Novato, CA 94945, USA., Campisi J; Buck Institute for Research on Aging, Novato, CA 94945, USA.
Jazyk: angličtina
Zdroj: Aging and disease [Aging Dis] 2024 May 07; Vol. 15 (3), pp. 1398-1415. Date of Electronic Publication: 2024 May 07.
DOI: 10.14336/AD.2023.0812
Abstrakt: 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.
Databáze: MEDLINE
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