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^].
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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