Role of the senescence associated factor dipeptidyl peptidase 4 in the pathogenesis of SARS CoV 2 infection

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 (ZO1), which contributes to epithelial barrier function. Mass spectrometry analysis indicated that DPP4 overexpressing cells exhibited a decrease in ZO1 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 ZO1 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.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Birgit Schilling  

PROVIDER: MSV000092495 | MassIVE | Fri Jul 21 11:16:00 BST 2023

SECONDARY ACCESSION(S): PXD043991

REPOSITORIES: MassIVE