Disruption of nuclear NAD+-SIR-2.1 axis by 6-PPD quinone is associated with induction of immunosuppression by modulating insulin signaling in Caenorhabditis elegans

The 6-PPDQ is an emerging contaminant ubiquitously detected in the environment and showing multiple aspects of toxicity on organisms. SIRT1 is a conserved NAD + -dependent deacetylase required for controlling stress response. In Caenorhabditis elegans , 0.1–10 μg/L 6-PPDQ reduced nuclear NAD + level, and decreased expressions of sir-2.1 encoding SIRT1 and nuclear SIR-2.1::mCherry, which could be reversed by treatment with NAD + precursors, such as nicotinic acid (NA) and nicotinamide (NAM). Intestinal RNAi of sir-2.1 exacerbated 6-PPDQ caused immunosuppression, whereas intestinal sir-2.1 overexpression prevented 6-PPDQ induced immunosuppression. Sir-2.1 RNAi upregulated insulin ligand genes and daf-2 , and inhibited daf-16 and its target genes. Genetic analyses confirmed that both DAF-16 and insulin ligands acted downstream of intestinal SIR-2.1 to regulated 6-PPDQ caused immunosuppression. Therefore, 6-PPDQ exposure disrupted intracellular NAD + homeostasis and inhibited nuclear SIR-2.1, which in turn enhanced 6-PPDQ caused immunosuppression by modulating the insulin signals.