Abstract
Senescence is a distinct set of changes in the senescence-associated secretory phenotype (SASP) and leads to aging and age-related diseases. Here, we screened compounds that could ameliorate senescence and identified an oxazoloquinoline analog (KB1541) designed to inhibit IL-33 signaling pathway. To elucidate the mechanism of action of KB1541, the proteins binding to KB1541 were investigated, and an interaction between KB1541 and 14–3–3ζ protein was found. Specifically, KB1541 interacted with 14–3–3ζ protein and phosphorylated of 14–3–3ζ protein at serine 58 residue. This phosphorylation increased ATP synthase 5 alpha/beta dimerization, which in turn promoted ATP production through increased oxidative phosphorylation (OXPHOS) efficiency. Then, the increased OXPHOS efficiency induced the recovery of mitochondrial function, coupled with senescence alleviation. Taken together, our results demonstrate a mechanism by which senescence is regulated by ATP synthase 5 alpha/beta dimerization upon fine-tuning of KB1541-mediated 14–3–3ζ protein activity.
Highlights
Somatic cells lose their ability to proliferate after a finite number of cell divisions, a phenomenon known as senescence [1]
An in-house compound library was treated on senescent fibroblasts and the effect on cell numbers was measured on day 12 (Figure 1A, Supplementary Tables 1 and 2)
A decrease in ATP production creates a bioenergetic imbalance by increasing the AMP to ATP ratio, resulting in cellular growth arrest and upregulation of senescence phenotypes [36]
Summary
Somatic cells lose their ability to proliferate after a finite number of cell divisions, a phenomenon known as senescence [1]. The hallmarks of senescence include permanent cell cycle arrest, marked changes in the morphology of organelles, and a senescenceassociated secretory phenotype (SASP) [2]. The most striking change during senescence is SASP, in which senescent cells secrete large amounts of inflammatory cytokines, immunomodulators and proteases [3]. Analysis of changes in the age-dependent gene expression profile of SASP revealed stage-specific SASP expression during senescence [4]. Immunosuppressive cytokines (characterized by TGFβ1 and TGF-β3) are released, but eventually inflammatory cytokines (characterized by IL-1β, IL-6, IL-8 and IL-33) are released [4]. Senescent cells change the neighboring microenvironment by gradually altering SASP expression
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