Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road

Abstract

Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is complex due to the combinatorial power of ~35 E2 and ~1000 E3 enzymes involved and the multiple lysine residues on ubiquitin that can be used to assemble polyubiquitin chains. Recently, mass spectrometric methods have identified that most enzymes in the ubiquitination cascade can be further modified through acetylation or phosphorylation under particular cellular conditions and altered modifications have been noted in different cancers and neurodegenerative diseases. This review provides a cohesive summary of ubiquitination, acetylation, and phosphorylation sites in ubiquitin, the human E1 enzyme UBA1, all E2 enzymes, and some representative E3 enzymes. The potential impacts these post-translational modifications might have on each protein function are highlighted, as well as the observations from human disease.

Non-lysine ubiquitylation: Doing things differently

“…Perhaps one of the most obvious benefits of expanding ubiquitylation to include residues beyond lysine is that it affords the opportunity for crosstalk with additional post-translational modifications (PTMs), at the same time avoiding competition with lysine-targeted PTMs such as acetylation, which has been reported to prevent substrate ubiquitylation and suppress isopeptide-linked ubiquitin chain formation ( Gronroos et al, 2002 ; Ito et al, 2002 ; Vervoorts et al, 2003 ; Bernassola et al, 2004 ; Jin et al, 2004 ; Simonsson et al, 2005 ; Le Cam et al, 2006 ; Min et al, 2010 ; Ohtake et al, 2015 ; Fan et al, 2022 ). The complex interplay between ubiquitylation and protein phosphorylation is well established and has been extensively reviewed elsewhere (see, for example, Hunter 2007 ; Chen and Chen 2013 ; Nguyen et al, 2013 ; Cohen 2014 ; Schwertman et al, 2016 ; Filipcik et al, 2017 ; Song and Luo 2019 ; Zhang and Zeng 2020 ; Dang et al, 2021 ; Lacoursiere et al, 2022 ). Therefore, the ability of ubiquitin to target the same hydroxylated residues as cellular kinases is an exciting development.…”

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

“…Ubiquitination largely affects lysine residues (Lacoursiere et al, 2022). This is catalysed by three enzymes, E1 (activates), E2…”

“…Acetylation of Lys and Arg (both basic) neutralises the side chain resulting in a larger residue with reduced polarity (green coloured in Figure 2) (Lacoursiere et al, 2022). There are at least 40 lysine acetyltransferases (Donev, 2021) and 20 deacetylases (Ho et al, 2020).…”

The Multifaceted Role of the Ubiquitin Proteasome System in Pathogenesis and Diseases

“…Last but not least, PTMs such as methylation, acetylation and phosphorylation are crucial in regulating various cellular processes [ 26 ]. Mass spectrometry-based proteomics studies are the key driving force that led to the detection of the majority of the PTM sites known to date [ 27 , 28 , 29 ].…”

“…In this issue, Lacoursiere and colleagues revealed the Ub and UPS PTM landscape, which was discovered through biochemical, biophysical, and proteomics assays. The potential impacts of these PTMs have on ubiquitin signaling are also discussed, along with implications in human diseases [ 26 ].…”