Beyond K48 and K63: non-canonical protein ubiquitination

Abstract

Protein ubiquitination has become one of the most extensively studied post-translational modifications. Originally discovered as a critical element in highly regulated proteolysis, ubiquitination is now regarded as essential for many other cellular processes. This results from the unique features of ubiquitin (Ub) and its ability to form various homo- and heterotypic linkage types involving one of the seven different lysine residues or the free amino group located at its N-terminus. While K48- and K63-linked chains are broadly covered in the literature, the other types of chains assembled through K6, K11, K27, K29, and K33 residues deserve equal attention in the light of the latest discoveries. Here, we provide a concise summary of recent advances in the field of these poorly understood Ub linkages and their possible roles in vivo.

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

“…Importantly, K48 chains can also be involved in non-proteolytic functions, while K63 chains, conversely, have known proteolytic functions [ 7 ]. The other five lysine linkages (K6, K11, K27, K29, and K33) are less well-studied, although this topic has recently been comprehensively reviewed [ 15 ]. Briefly, K6-linked poly-Ub chains have been shown to be involved in autophagy and the DNA damage response; K11 chains are implicated in cell cycle regulation and proteasomal degradation or stabilization; K27 chains are important actors in the innate immune response; K29 chains are involved in cell signaling, with potentially protective roles in neurodegenerative diseases; and K33 chains have purported roles in cell signaling and protein trafficking.…”

Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development

“…The seven internal lysines within ubiquitin and the N-terminal methionine can also serve as ubiquitin acceptors, giving rise to di/tri/polyubiquitin chain formation and extension. K48-linked chains are classically associated with promoting target degradation through the ubiquitin proteasome system (UPS), but the variety of potential modification types and chain topologies affords significant signalling complexity, altering the interaction landscape and conferring various possible outcomes on client proteins [ 21 , 22 ].…”

Stem cells for the treatment of glioblastoma: a 20-year perspective

“…The lack of standardized protocols and methods to characterize therapeutic stem cells can lead to therapeutic failures and decreased confidence in this promising strategy. Indeed, MSCs are referred to as a ‘double-edged sword’ as a result of their ability to both promote and inhibit tumor growth [ 80 ]. An increasing number of scientists point to the need to thoroughly characterize this heterogeneous population of cells and establish gold standards for the derivation and use of MSCs – standards shared between researchers, clinicians and industry – to allow for proper comparison between different studies and for scientific progress [ 81 ].…”