||Kazuhito Gotoh, Takafumi Morisaki, Daiki Setoyama, Katsuhiko Sasaki, Mikako Yagi, Ko Igami, Soichi Mizuguchi, Takeshi Uchiumi, Yoshinori Fukui, Dongchon Kang, Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation, Cell Reports, https://doi.org/10.1016/j.celrep.2018.10.057, VOLUME 25, ISSUE 7, 1800-1805, 2018.11, Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases. Although mitochondrial metabolic pathways are essential for DC activation, the precise molecular mechanism remains poorly understood. Gotoh et al. show that mitochondrial p32/C1qbp supports dendritic cell metabolism and maturation. In addition, mitochondrial p32 and pyruvate dehydrogenase activity are necessary for DC maturation in vitro and in vivo..
||Sasaki, Katsuhiko, Gotoh, Kazuhito, Sho Miake, Setoyama, Daiki, Yagi, Mikako, Igami, Ko, Uchiumi, Takeshi, Kang, Dongchon, p32 is Required for Appropriate Interleukin- 6 Production Upon LPS Stimulation and Protects Mice from Endotoxin Shock, EBIOMEDICINE, 20, 161-172, 2017.06, Sepsis is a major cause of morbidity and mortality in seriously ill patients and mitochondrial dysfunction is associated with poor outcomes in septic patients. Although interleukin-6 (IL-6) is a good prognostic marker for sepsis, the relationship between mitochondrial dysfunction and IL-6 remains poorly understood. We identified p32/C1QBP/HABP1 as a regulator of IL-6 production in response to lipopolysaccharide (LPS). LPS induced IL-6 overproduction in p32 deficient mouse embryonic fibroblasts (MEFs) through NF-κB independent but activating transcription factor (ATF) 4 dependent pathways. Short hairpin RNA-based knockdown of ATF4 in p32 deficient MEFs markedly inhibited LPS-induced IL-6 production. Furthermore, MEFs treated with chloramphenicol, an inhibitor of mitochondrial translation, produced excessive IL-6 via ATF4 pathways. Using a LPS-induced endotoxin shock model, mice with p32 ablation in myeloid cells showed increased lethality and overproduction of IL-6. Thus, this study provides a molecular link how mitochondrial dysfunction leads to IL-6 overproduction and poor prognosis of sepsis..