A functional connection between RanGTP, NF-kappaB and septic shock

RanGTPase is importantly involved in diverse biological functions, such as nuclear transport, spindle formation during mitosis, DNA replication and cell division. This review summarizes yet another new role of Ran - control of the activity of NF-kappaB in host immune responses. Overexpression of a specific allele of Ran results in preferential accumulation of nuclear RanGTP, downmodulation of proinflammatroy cytokine production and protection against septic shock. Nuclear RanGTP interacts with Exportin1, which in turn binds to IkappaB. Nuclear IkappaB binds to NF-kappaB in the nucleus, inhibiting NF-kappaB transcriptional activation of proinflammatory cytokine genes. Nuclear IkB also functions as an adaptor between NF-kappaB and Exportin1/RanGTP, enhancing export of NF-kappaB to the cytoplasm and further reducing the magnitude of host immune responses. From this picture, it appears that modulation of host immune responses via RanGTPase will have an immense impact on a wide spectrum of emerging infectious diseases, cancer and other genetic diseases.