Lysine 63 polyubiquitination in immunotherapy and in cancer-promoting inflammation

Abstract

Covalent and reversible post-translational modifications of proteins are a common theme in signaling. Ub iquitin conjugation was originally described to target proteins to proteasomal degradation by ubiquitin polymerization involving lysine (K) 48 residues. Di fferently linked polymers of polyubiquitin have been found that modify proteins without targeting to proteasomal degradation. In stead this pathway creates docking sites for signaling scaffolds that are key to control the nuclear factor-κB (NF-κB) pathway. I ndeed TRAF-2, TRAF-6, and TRAF-3 are E3 ubiquitin ligases that form K63-linked ubiquitin polymers. Therefore signaling via TNF family receptors, IL1R, IL-18R, T-cell receptor (TCR), and Toll-like receptors (TLR) use this type of post-translational modification. Specific enzymes exist (DUBs) that deactivate this system, degrading K63 polyubiquitin chains. Interestingly, mice deficient in these deubiquitinases develop autoimmunity and inflammation. In carcinogenesis, the K63 polyubiquitin pathway is possibly critical for inflammation-driven tumor promotion. The pathway is also critically involved in costimulation of tumor immunity/immunotherapy as well as in the biology of malignant cells themselves. The elements of this new signaling paradigm offer the opportunity for therapeutic exploitation and drug discovery. © 2009 American Association for Cancer Research.