NAG-1/GDF15 Accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway

Protein dynamics, modifications, and trafficking are all processes that can modulate protein activity. Accumulating evidence strongly suggests that many proteins play distinctive roles dependent on cellular location. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) is a TGF-β superfamily protein that plays a role in cancer, obesity, and inflammation. NAG-1 is synthesized and cleaved into a mature peptide, which is ultimately secreted into the extracellular matrix (ECM). In this study, we have found that full-length NAG-1 is expressed in not only the cytoplasm and ECM, but also in the nucleus. NAG-1 is dynamically moved to the nucleus, exported into cytoplasm, and further transported into the ECM. We have also found that nuclear NAG-1 contributes to inhibition of the Smad pathway by interrupting the Smad complex. Overall, our study indicates that NAG-1 is localized in the nucleus and provides new evidence that NAG-1 controls transcriptional regulation in the Smad pathway.