SAA4: An Underdog Within the Serum Amyloid a Superfamily?

Non-glycosylated liver-derived acute-phase amyloid A1 and A2 proteins (SAA1 and SAA2, 104 amino acids), generated by two different genes in humans (SAA1/2) and other mammalian species, are considered the prime acute-phase reactants following inflammatory conditions during host defense in cells, tissues, and the circulation. While human SAA3 has been identified as a pseudogene, Saa3 genes in other mammalian species are coding for primarily extrahepatically expressed Saa3 proteins that also may act as suitable inflammatory markers. The discovery of SAA4 (112 amino acids, carrying an octapeptide insert) in humans and mice has paved a new avenue for the exploration of different functions of this so far unknown member of the SAA superfamily. SAA4 has originally been termed a “constitutively” expressed SAA protein, apparently due to its nature not to act as an inflammatory marker. The present overview aimed to cover possible functions—so far identified—for human SAA4 (following its expression in various diseases on mRNA and protein level) and to work out whether SAA4 might be considered—at least in part—an acute-phase protein. Alternatively, we are raising the question whether SAA4 may solely act as a bystander or even underdog within the whole SAA family, where SAA1 and SAA2 proteins (commonly termed acute-phase SAA) hold undoubtedly an eminent status during inflammatory conditions, not only as host defense reactants but also as long-lasting markers for chronic diseases and malignancies in humans.