The role of ubiquitination in health and disease

Abstract

Ubiquitination is an enzymatic process characterized by the covalent attachment of ubiquitin to target proteins, thereby modulating their degradation, transportation, and signal transduction. By precisely regulating protein quality and quantity, ubiquitination is essential for maintaining protein homeostasis, DNA repair, cell cycle regulation, and immune responses. Nevertheless, the diversity of ubiquitin enzymes and their extensive involvement in numerous biological processes contribute to the complexity and variety of diseases resulting from their dysregulation. The ubiquitination process relies on a sophisticated enzymatic system, ubiquitin domains, and ubiquitin receptors, which collectively impart versatility to the ubiquitination pathway. The widespread presence of ubiquitin highlights its potential to induce pathological conditions. Ubiquitinated proteins are predominantly degraded through the proteasomal system, which also plays a key role in regulating protein localization and transport, as well as involvement in inflammatory pathways. This review systematically delineates the roles of ubiquitination in maintaining protein homeostasis, DNA repair, genomic stability, cell cycle regulation, cellular proliferation, and immune and inflammatory responses. Furthermore, the mechanisms by which ubiquitination is implicated in various pathologies, alongside current modulators of ubiquitination are discussed. Enhancing our comprehension of ubiquitination aims to provide novel insights into diseases involving ubiquitination and to propose innovative therapeutic strategies for clinical conditions.

Keywords: protein degradation; protein homeostasis; ubiquitin; ubiquitination.

FIGURE 1

Overview of the ubiquitination process (by Figdraw). Ubiquitination is an enzyme‐catalyzed reaction that plays a crucial role in various biological processes. Substrates are tagged with ubiquitin and transported to the proteasome for degradation, while ubiquitin molecules are recycled by deubiquitinating enzymes.

FIGURE 2

Overview of the ubiquitin chain types (by Figdraw). Different types of ubiquitin chains: monoubiquitination and polyubiquitination. Polyubiquitin chains can be homotypic or heterotypic, indicating the uniformity or diversity in the linkage types within the chain.

FIGURE 3

Ubiquitin‐mediated protein trafficking and localization (by Figdraw). (A) Ubiquitin‐mediated protein degradation in the endoplasmic reticulum (ER) involves tagging misfolded proteins for transport to the proteasome. (B) Ubiquitination facilitates the reorganization of COPII vesicles, allowing them to form larger vesicles capable of accommodating substrates. (C) In the Golgi apparatus, ubiquitination mediates the relocation and transport of proteins. (D) Ubiquitin‐mediated transport of proteins within the nucleus ensures proper protein localization and function. Dub, deubiquitinases; NPC, nuclear pore complex; ER, endoplasmic reticulum.

FIGURE 4

Ubiquitination in key signaling pathways (by Figdraw). (A) Ubiquitination in canonical and noncanonical NF‐κB signaling pathways, regulating the activation and translocation of NF‐κB subunits. (B) Types and structures of NF‐κB, including its various subunits and their functional domains. (C) Ubiquitination in the Wnt‐β‐catenin signaling pathway, influencing the stability and activity of β‐catenin. (D) Ubiquitination in the EGFR signaling pathway, affecting receptor trafficking, degradation, and downstream signaling. TCF, T‐cell factor; LEF, lymphoid enhancer factor; LRP, lipoprotein receptor‐related protein; GSK3, glycogen synthase kinase 3; β‐TrCP, beta‐transducin repeat‐containing protein; RHD, Rel homology domain; TAD, transactivation domains; NIK, NF‐κB‐inducing kinase; cIAP, cellular inhibitor of apoptosis; IKK, IκB kinase; EGFR, epidermal growth factor receptor; P, phosphorylation; Ub, ubiquitin.

FIGURE 5

Ubiquitination in DNA repair (by Figdraw). (i) Involvement in DNA double‐strand break repair; (ii) role in DNA crosslink repair; (iii) participation in transcription‐coupled nucleotide excision repair. RNF, ring finger protein; BRCA1, breast cancer type 1; BARD1, BRCA1‐associated RING domain protein 1; Ub, ubiquitin.

FIGURE 6

Ubiquitination in cell cycle regulation and genome stability (by Figdraw). (i and ii) APC/C in cell cycle regulation; (iii–v) ubiquitination in the regulation of G1/S transition; (vi and vii) ubiquitination in the regulation of G2/M transition. SAC, spindle assembly checkpoint; Sgo2, shugoshin 2; Mad2, mitotic‐arrest deficient‐1; hSSB1, human single‐stranded DNA binding protein SSB1; NUCKS1, nuclear casein and cyclin‐dependent kinase substrate 1; SKP2, S‐phase kinase‐associated protein 2; APC/C, anaphase‐promoting complex/cyclosome; CDKs, cyclin‐dependent kinases; Cdc20, cell‐division cycle protein 20 homologue; Cdh1, E‐cadherin gene; P, phosphorylation; Ub, ubiquitin.

FIGURE 7

Ubiquitination in inflammation regulation (by Figdraw). (i–iv) Ubiquitination and TCR signaling; (v–vii) ubiquitination in B cell differentiation; (viii) ubiquitination in conjunction with AP‐1 in inflammation regulation; (ix) ubiquitination in cell death (pyroptosis). TCR, T cell receptor; Shp‐1, SH2 domain‐containing protein tyrosine phosphatase 1; WWP2, WW domain‐containing protein 2; YY1, Yin Yang 1; AP‐1, activator protein‐1; GSDMD, gasdermin D; P, phosphorylation; Ub, ubiquitin.