Extracellular ubiquitin: immunemodulator and endogenous opponent of damage-associated molecular pattern molecules

Ubiquitin is a post-translational protein modifier and plays essential roles in all aspects of biology. Although the discovery of ubiquitin introduced this highly con-served protein as a molecule with extracellular actions, the identification of ubiquitin as the ATP-dependent pro-teolysis factor 1 has focused subsequent research on its important intracellular functions. Little attention has since been paid to its role outside of the cell. During re-cent years, multiple observations suggest that extra-cellular ubiquitin can modulate immune responses and that exogenous ubiquitin has therapeutic potential to attenuate exuberant inflammation and organ injury. These observations have not been integrated into a comprehensive assessment of its possible role as an endogenous immune modulator. This review recapitu-lates the current knowledge about extracellular ubiq-uitin and discusses an emerging facet of its role in biol-ogy during infectious and noninfectious inflammation. The synopsis of these data along with the recent identi-fication of ubiquitin as a CXCR4 agonist suggest that extracellular ubiquitin may have pleiotropic roles in the immune system and functions as an endogenous oppo-nent of DAMPs. Functions of extracellular ubiquitin could constitute an evolutionary conserved control mechanism aimed to balance the immune response and prevent exuberant inflammation. Further charac-terization of its mechanism of action and cellular signal-ing pathways is expected to provide novel insights into the regulation of the innate immune response and op-portunities for therapeutic interventions. J. Leukoc. Biol. 89: 205–219; 2011