The involvement of Ran GTPase in lipopolysaccharide endotoxin-induced responses

By functional cloning, we have established that Ran GTPase is involved in L PS-induced signal transduction. This has been accomplished by several funct ional comparisons of the two cDNAs, Lps(n)/Ran (or RanT/n) and Lps(d)/Ran ( or RanC/d), which were isolated from cDNA libraries of LPS responder and hy poresponder mice, respectively. The letter n refers to the 'normal' phenoty pe and the letter d refers to the 'deficient' phenotype. Consistent with ou r previous results, more animal studies indicated that adenoviral transduct ion of RanC/d cDNA, but not RanT/n cDNA, into sensitive mice conferred sign ificant resistance against endotoxin challenge. Thus the incorporation of R anC/d cDNA into gene therapy protocols as a therapeutic sequence remains ve ry attractive. At steady state, hematopoietic cells transduced with RanC/d cDNA led to about a IO-fold increase in exogenous Ran protein compared with RanT/n cDNA. Furthermore, our cumulative data suggest that a slight elevat ion of Ran protein in B cells enhances LPS responsiveness, but the same ele vation of Ran in macrophages does not. On the other hand, a high level of o verexpression of Ran in both macrophages and B cells down-regulates LPS sig nal transduction. Thus LPS-induced signal transduction in macrophages and B cells is likely to occur via different signaling pathways.