The Role of Lysine 63-Linked Ubiquitylation in Health and Disease

Abstract

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.

Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation

“…Polyubiquitin chains linked via lysine 63 (K63) mediate diverse cellular processes including DNA repair and numerous immune and inflammatory responses (Isaacson and Ploegh, 2009;Pontrelli et al, 2019). K63 ubiquitin (K63-Ub) chains are essential as a non-degradative signal activated by signal transduction pathways that culminate in the activation of master transcription regulators such as nuclear factor kB (NF-kB) and interferon regulatory factor 3 (IRF3).…”

MAPK dependent regulation of FBXW7 phosphodegrons

“…Heterotypic Lys11 polyubiquitin chain is also known to be involved in protein degradation [64]. Whereas Lys63 linked polyubiquitin chain functions as a non-degradative tag allowing the formation of signalling complexes for various cellular processes such as DNA repair, innate immune response, activation of transcription factors, protein sorting and removing the damaged mitochondria [65]. Moreover, the ubiquitin moieties can be modified by phosphorylation on its serine, threonine or tyrosine residues by cellular stress such as mitochondrial damage [66,67].…”