The mysterious polyamines, the enigmatic Barr body, and lupus: comment on the article by Kim et al

"Polyamine patterns in plasma of patients with systemic lupus erythematosus and fever" by Kim et al. provides insight into possible involvement of polyamines in systemic lupus erythematosus (SLE). The authors report decreases in N1-acetylspermidine, spermidine, spermine, and N1-acetylcadaverine and increased cadaverine in SLE. Polyamine involvement in many cellular processes and their unique characteristics (high charge, length, flexibility, and ubiquity) give polyamines importance in health and disease. In this editorial, I describe a scenario, the "X chromosome-nucleolus nexus" hypothesis, in which polyamines could initially rise because of cellular stress. This rise in polyamines increases nucleolar size and activity. Polyamines are critical in the nucleolar assembly of ribonucleoprotein complexes, such as ribosomes. However, the expanding nucleolus could disrupt a neighboring inactive X chromosome (Barr body). This disruption opens additional polyamine genes that alter polyamine levels and types through wasteful synthesis and recycling of polyamines. This could include a decrease in the key polyamines spermidine and spermine, which are critical to nucleolar functioning. And this can decrease S-adenosylmethionine needed for cellular methylation leading to hypomethylation seen in SLE. As a result, the nucleolus can no longer respond properly to future stresses. With altered polyamine levels and types in the nucleolus, many RNA transcripts, proteins, and ribonucleoprotein complexes assembled in the nucleolus may be trapped in autoantigenic conformations. Many of the major autoantigens in SLE are, at least transiently, components of the nucleolus. Therefore, the observations of decreased polyamines reported by Kim et al. could be important in the formation of autoantigens.