tetano
Editor, Senior Moderator
Aging Dis
. 2023 Sep 3.
doi: 10.14336/AD.2023.0812. Online ahead of print. Role of the Senescence-Associated Factor Dipeptidyl Peptidase 4 in the Pathogenesis of SARS-CoV-2 Infection
Stefanie Deinhardt-Emmer[SUP] 1 2 [/SUP], Sharvari Deshpande[SUP] 1 [/SUP], Koji Kitazawa[SUP] 1 [/SUP], Allison B Herman[SUP] 3 [/SUP], Joanna Bons[SUP] 1 [/SUP], Jacob P Rose[SUP] 1 [/SUP], Prasanna Ashok Kumar[SUP] 1 [/SUP], Carlos Anerillas[SUP] 3 [/SUP], Francesco Neri[SUP] 1 [/SUP], Serban Ciotlos[SUP] 1 [/SUP], Kevin Perez[SUP] 1 [/SUP], Nilay Köse-Vogel[SUP] 2 [/SUP], Antje Häder[SUP] 2 [/SUP], Kotb Abdelmohsen[SUP] 3 [/SUP], Bettina Löffler[SUP] 2 [/SUP], Myriam Gorospe[SUP] 3 [/SUP], Pierre-Yves Desprez[SUP] 1 [/SUP], Simon Melov[SUP] 1 [/SUP], David Furman[SUP] 4 5 [/SUP], Birgit Schilling[SUP] 1 [/SUP], Judith Campisi[SUP] 1 [/SUP]
Affiliations
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.
. 2023 Sep 3.
doi: 10.14336/AD.2023.0812. Online ahead of print. Role of the Senescence-Associated Factor Dipeptidyl Peptidase 4 in the Pathogenesis of SARS-CoV-2 Infection
Stefanie Deinhardt-Emmer[SUP] 1 2 [/SUP], Sharvari Deshpande[SUP] 1 [/SUP], Koji Kitazawa[SUP] 1 [/SUP], Allison B Herman[SUP] 3 [/SUP], Joanna Bons[SUP] 1 [/SUP], Jacob P Rose[SUP] 1 [/SUP], Prasanna Ashok Kumar[SUP] 1 [/SUP], Carlos Anerillas[SUP] 3 [/SUP], Francesco Neri[SUP] 1 [/SUP], Serban Ciotlos[SUP] 1 [/SUP], Kevin Perez[SUP] 1 [/SUP], Nilay Köse-Vogel[SUP] 2 [/SUP], Antje Häder[SUP] 2 [/SUP], Kotb Abdelmohsen[SUP] 3 [/SUP], Bettina Löffler[SUP] 2 [/SUP], Myriam Gorospe[SUP] 3 [/SUP], Pierre-Yves Desprez[SUP] 1 [/SUP], Simon Melov[SUP] 1 [/SUP], David Furman[SUP] 4 5 [/SUP], Birgit Schilling[SUP] 1 [/SUP], Judith Campisi[SUP] 1 [/SUP]
Affiliations
- PMID: 37728586
- 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.