A specific subfamily within the E2 protein family is involved in the synthesis of noncanonical poly-ubiquitin chains, linked through lysine 63 residues. The role of lysine 63-linked polyubiquitylation in diseases has emerged only recently. Under physiological conditions, this process does not seem to be involved in the classical protein degradation by the proteasome, but it is involved in the regulation of intracellular signaling, DNA damage response, cellular trafficking, and lysosomal targeting. The alteration of this process has been described in a number of pathological conditions, including immune disorders, diabetes, and cancer. In this chapter, we will describe the role of lysine 63-linked ubiquitylation in the regulation of diverse signaling pathways involved in cell behavior. We will also describe some pathological conditions in which altered lysine 63-linked ubiquitylation has been referred to play an important role.
Part of the book: Ubiquitin Proteasome System