Activation of Thiamine Pyrophosphokinase TPK-1 Contributes to 6-PPD Quinone-Induced Immunosuppression by Inhibiting Mitochondrial UPR in Caenorhabditis elegans.

As an emergent contaminant, 6-PPD quinone (6-PPDQ) causes toxic effects in organisms, including induction of immunosuppression. Thiamine pyrophosphate (TPP) serves as an important cofactor for some metabolisms. We aimed to examine the role of thiamine pyrophosphokinase TPK-1 in modulating 6-PPD-induced immunosuppression. Using Caenorhabditis elegans as the animal model, 6-PPDQ-exposure treatment was applied to nematodes from the L1 larval stage to adult day 3, and innate immune response was assessed by the expression of antimicrobial genes. In nematodes, 6-PPDQ (1-10 μg/L) elevated TPP content, which was due to an increase in the expression of tpk-1, and RNAi of tpk-1 could block 6-PPDQ-induced immunosuppression. Meanwhile, RNAi of tpk-1 strengthened expressions of mitochondrial UPR (mt UPR) marker genes (hsp-6 and hsp-60) by activating three transcription factor (TF) genes (atfs-1, ubl-5, and dve-1) in 6-PPDQ-exposed nematodes. RNAi of mitochondrial UPR marker genes and three TF genes aggravated 6-PPDQ-induced immunosuppression. TPK-1 acted upstream of these three TF genes to modulate 6-PPDQ-induced immunosuppression. Moreover, RNAi of tpk-1 inhibited the expression of complex III/IV subunit genes, and RNAi of these complex III/IV subunit genes conferred resistance to 6-PPDQ-induced immunosuppression. Additionally, these complex III/IV subunit genes functioned upstream of TF genes (atfs-1, ubl-5, and dve-1) to regulate 6-PPDQ-induced immunosuppression. Therefore, our data provide a novel basis for 6-PPDQ-induced immunosuppression mediated by activation of TPK-1 and the following mt UPR suppression.