Metabolic Functions of the Murine Lupus Susceptibility Gene Pbx1
- Roach, Tracoyia A.; Titov, Anton; Soh, Sujung; Robusto, Brian; Morel, Laurence
- Issue Date
- AMER ASSOC IMMUNOLOGISTS
- JOURNAL OF IMMUNOLOGY, v.200, no.1 suppl.
- Journal Title
- JOURNAL OF IMMUNOLOGY
- 1 suppl.
- Systemic Lupus Erythematosus (SLE) is an autoimmune disease that affects many organ systems. Poorly characterized genetic factors contribute to SLE, in part through the production of autoreactive or inflammatory T cells. Pre-B cell leukemia homeobox 1 (Pbx1) is a transcription factor whose Pbx1-d dominant negative splice isoform is overexpressed in CD4T cells of lupus patients as well as in the NZM2410 lupus-prone mouse as compared to the normal Pbx1-b isoform. Based on gene expression studies comparing murine CD4 T cells overexpressing Pbx1-d to controls, we hypothesize that Pbx1-d enhances cellular metabolism in T cells through the HIF1α and mTORc1 pathways. CD4 T cells expressing Pbx1-d present a higher cellular metabolism and show a higher mTORc1 activation than normal control T cells. Using mesenchymal stem cells, we showed that transfection of Pbx1-d was sufficient to increase glycolysis, a pathway linked to T cell activation. We found that Ddit4, an mTORc1 inhibitor, shows a lower expression in the Pbx1-d-expressing CD4 T cells than in normal T cells. We also discovered that Pbx1-d preferentially binds to the promoter of Ddit4, as well as Egln1 and Egln3, two HIF1a inhibitors. These results suggest that a mechanism by which the Pbx1-d allele contributes to lupus pathogenesis is to enhance CD4 T cell metabolism. Future work will define how Pbx1 controls the immune system and how the function of this transcription factor is linked to cellular metabolism.
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