Identify the Cellular Location Where PDC is Most Active

Signal transducer and activator of transcription (STAT) proteins are essential in cellular responses to cytokines and growth factors. They act as latent cytoplasmic transcription factors [^1^]. When a ligand binds to the receptor, STAT proteins become tyrosine-phosphorylated, dimerize, and translocate to the nucleus. There, they regulate the expression of various target genes [^2^][^3^].

Among the STAT family members, STAT3, STAT5a, and STAT5b (collectively called STAT5) play a crucial role in regulating cell cycle, apoptosis resistance, and negative feedback control [^4^]. Co-factors in the nucleus can regulate STAT activity [^5^]. Transcriptional co-activators like p300/CBP, Nmi, and NCoA-1 upregulate STAT3- and/or STAT5-dependent gene expression by directly interacting with STAT proteins [^6^][^7^][^8^][^9^]. Conversely, STAT-mediated gene regulation can be suppressed by binding co-repressors to STAT proteins. For instance, PIAS3 and SMRT bind to STAT3 and STAT5, respectively, inhibiting their transactivating functions [^10^][^11^].

Interestingly, GRIM-19, a growth suppressive gene in the cell death pathway induced by interferon-β and retinoic acid treatment, represses STAT3-mediated gene expression [^12^][^13^]. GRIM-19 is a subunit of complex I in the electron transport chain (ETC) and is crucial for its assembly in the inner mitochondrial membrane [^14^][^15^][^16^]. Although GRIM-19 is primarily located in the mitochondrion, a small amount can be detected in the cytoplasm and nucleus. Cytosolic GRIM-19 blocks STAT3 nuclear translocation, while nuclear GRIM-19 inhibits STAT3-dependent gene transcription. This association between GRIM-19 and STAT3 is specific and does not occur with other STAT family members [^12^][^13^].

Recently, we discovered a novel STAT5-interacting partner called the E2 subunit of pyruvate dehydrogenase complex (PDC-E2) [^17^]. PDC-E2, like many mitochondrial proteins, is encoded by the nuclear genome, translated in the cytoplasm, and translocated to the mitochondrial matrix [^18^][^19^]. Processed PDC-E2 self-assembles with other proteins to form a large complex involved in cellular metabolism [^20^][^21^][^22^][^23^][^24^].

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Aside from its role in cellular metabolism, PDC-E2 is also the primary autoantigen in primary biliary cirrhosis (PBC), an autoimmune disease affecting the intrahepatic bile ducts [^25^][^26^]. In PBC patients, abnormal expression of PDC-E2 has been observed on the surface of biliary epithelial cells [^27^]. However, its exact nature as an autoantigen remains unclear. This raises questions about whether PDC-E2 performs other physiological functions outside the mitochondrion in different cell types. In this study, we investigate the role of PDC-E2 in the nucleus and specifically its involvement in STAT5-dependent gene expression in response to interleukin-3 (IL-3).

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