G-protein pathway suppressor 2 (GPS2) is a 36kD protein involved in a number of regulatory functions in key metabolic organs. First discovered as a suppressor of the RAS- and MAPK- signaling pathways, GPS2 is subsequently identified as part of the NCoR/SMRT corepressor complex that play an important regulatory role in gene transcription, and GPS2 is also involved in meiotic recombination in the nucleus. Recently, we identified a non-transcriptional role of GPS2 as an inhibitor of the pro-inflammatory JNK pathway activation in response to tumor necrosis factor alpha (TNF-a;) in the cytosol. This suggests that GPS2 function may be dependent on its cellular localization. However, an understanding of how GPS2 differentially target cellular compartments is still lacking. In this study, we show that a tightly controlled balance between GPS2 protein stabilization and degradation regulates the function of nuclear GPS2. Our results reveal that methylation by arginine methyltransferase PRMT6 and interaction with exchange factor TBL1 cooperate to protect GPS2 from Siah2-dependent proteasomal degradation, thus promoting GPS2 nuclear localization. In addition, our results link GPS2 protein instability to decreased nuclear-encoded mitochondrial gene expression, suggesting that GPS2 may play an important role in regulating mitochondrial oxidative capacity, whose imbalance has been linked to chronic inflammation and insulin resistance. In conclusion, our findings illustrate post-transcriptional modification is important in the regulation of GPS2 cellular function. Understanding such molecular regulation of GPS2 is critical in furthering future efforts to investigate its roles in cellular homeostasis and inflammatory responses.