Oxidative stress has been implicated in the pathogenesis of numerous diseases. Redox sensing mechanisms and regulation of redox-responsive transcription factors are required to detect and respond to oxidative threats. The transcription factor, nuclear factor κB (NF-κB) is a ubiquitous cellular regulator widely recognized as a critical mediator of intracellular signaling for immune and inflammatory response. Complex regulatory networks exist to ensure that NF-κB is only activated by appropriate stimuli and is then inactivated when no longer needed. NF-κB typically resides in the cytoplasm in an apparently inhibited state bound with an inhibitory protein known as IκBα. It has been established that NF-κB activation is first achieved by phosphorylation of the inhibitory protein IκBα to release NF-κB to their free forms. Once released, NF-κB proteins are translocated to the nucleus where, with the help of co-regulators, they will coordinate the cascade signaling responses to the external stimuli. At present, the precise roles played by co-regulators in the cell nucleus are poorly understood. In this presentation, I will describe our findings on the redox-sensing role of a non-heme Fe protein, Pirin, for NF-κB proteins. Pirin is a non-heme iron protein expressed in human tissues that, at its ferric oxidation state, forms tight complexes with inducible transcription factor NF-κB proteins and by doing so greatly modulates the transcriptional regulation activities of NF-κB (Liu et al., PNAS 2013, 110, 9722-9727). By performing biochemical, spectroscopic, and structural studies, a novel regulation mechanism is proposed. I will also present our latest progress in our molecular and cellular studies.
Prof. Amit Reddi (404-385-1428)