TIGAR coordinates senescence-associated secretory phenotype via lysosome repositioning and α-tubulin deacetylation

Abstract

TP53-induced glycolysis and apoptosis regulator (TIGAR) regulates redox homeostasis and provides the intermediates necessary for cell growth by reducing the glycolytic rate. During cellular senescence, cells undergo metabolic rewiring towards the glycolytic pathway, along with the development of the senescence-associated secretory phenotype (SASP), also known as the secretome. We observed that TIGAR expression increased during replicative senescence following the in vitro expansion of human mesenchymal stromal cells (MSCs) and that TIGAR knockout (KO) decreased SASP factors and triggered premature senescence with decelerated progression. Additionally, TIGAR KO impaired flexible lysosomal movement to the perinuclear region and decreased the autophagic flux of MSCs. Research on the mechanism of lysosomal movement revealed that, while native senescent MSCs presented low levels of Ac-α-tubulin (lysine 40) and increased sirtuin 2 (SIRT2) activity compared with those in growing cells, TIGAR KO-MSCs maintained Ac-α-tubulin levels and exhibited decreased SIRT2 activity despite being in a senescent state. The overexpression of SIRT2 reduced Ac-α-tubulin as a protein target of SIRT2 and induced the positioning of lysosomes at the perinuclear region, restoring the cytokine secretion of TIGAR KO-MSCs. Furthermore, TIGAR expression was positively correlated with SIRT2 activity, indicating that TIGAR affects SIRT2 activity partly by modulating the NAD+ level. Thus, our study demonstrated that TIGAR provides a foundation that translates the regulation of energy metabolism into lysosome positioning, affecting the secretome for senescence development. Considering the functional value of the cell-secretome in aging-related diseases, these findings suggest the feasibility of TIGAR for the regulation of secretory phenotypes. Cellular senescence is a process where cells stop dividing due to stress. Researchers found that the protein TIGAR plays a role in this process, but its exact function was unclear. In this study, researchers explored how TIGAR affects cellular senescence. They used mesenchymal stromal cells from human umbilical cord blood and conducted experiments to knock out TIGAR using CRISPR-Cas9 technology. They found that knocking out TIGAR led to early onset but slower progression of senescence. TIGAR knockout cells showed changes in lysosome positioning, reduced autophagic flux, and altered secretion of cytokines. These changes were linked to the acetylation of α-tubulin, a protein that helps in cell structure and transport. The results suggest that TIGAR regulates cellular senescence by affecting lysosome positioning and autophagy through SIRT2, an enzyme that deacetylates α-tubulin. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.