Immune Regulation by Ubiquitin Tagging as Checkpoint Code

The immune system is equipped with effective machinery to mobilize its activation to defend invading microorganisms, and at the same time, to refrain from attacking its own tissues to maintain immune tolerance. The balance of activation and tolerance is tightly controlled by diverse mechanisms, since breakdown of tolerance could result in disastrous consequences such as the development of autoimmune diseases. One of the mechanisms is by the means of protein ubiquitination, which involves the process of tagging a small peptide ubiquitin to protein substrates. E3 ubiquitin ligases are responsible for catalyzing the final step of ubiquitin-substrate conjugation by specifically recognizing substrates to determine their fates of degradation or functional modification. The ubiquitination process is reversible, which is carried out by deubiquitinating enzymes to release the ubiquitin molecule from the conjugated substrates. Protein ubiquitination and deubiquitination serve as checkpoint codes in many key steps of lymphocyte regulation including the development, activation, differentiation, and tolerance induction. In this chapter, we will discuss a few E3 ligases and deubiquitinating enzymes that are important in controlling immune responses, with emphasis on their roles in T cells.