Ubiquitination Mechanisms in Inflammatory and Cancer Biology

Ubiquitination is a reversible post-translational modification that controls protein fate through attachment of ubiquitin chains by coordinated action of E1 activating enzymes, E2 conjugating enzymes and E3 ubiquitin ligases, with removal by deubiquitinases. In inflammation, diverse linkage types govern signal transduction from pattern-recognition receptors to cytokine production, inflammasome activation and nuclear factor-κB (NF-κB) transcriptional programmes. Aberrant ubiquitination of key signalling intermediates can drive chronic inflammatory diseases. In cancer, dysregulated ubiquitin-mediated degradation of tumour suppressors or stabilisation of oncoproteins underlies malignant transformation, metastasis and immune evasion. Linear and K63-linked chains assemble scaffolds for kinase complexes, while K48 linkages target proteins for proteasomal destruction. Crosstalk with autophagy, DNA repair and cell-cycle checkpoints integrates ubiquitination into cellular quality control. Emerging strategies such as proteolysis targeting chimeras and molecular glues exploit E3 ligases to eliminate pathogenic factors. Collectively, advances in structural biology, enzymology and chemical biology are illuminating how ubiquitin-mediated pathways orchestrate immunity and tumour biology, yielding novel therapeutic avenues in inflammatory and oncological settings.

Research from Nature Portfolio

Recent studies have revealed the structural basis of UFMylation, a ubiquitin-like modification, on 60S ribosomal subunits stalled at the endoplasmic reticulum. High-resolution cryo-electron microscopy of the UFM1 ribosome E3 ligase complex demonstrates how it encloses the 60S subunit, remodels the peptidyl transferase centre and switches from ‘writer’ to ‘reader’ of its own modification. These insights establish UFMylation as a critical regulator of ribosome release and protein homeostasis at the ER, with potential implications for the regulation of secretory pathways in both inflammation and cancer.

Ubiquitination Mechanisms in Inflammatory and Cancer Biology publication trend

The graph below shows the total number of articles in ubiquitination mechanisms in inflammatory and cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Ubiquitination: Covalent attachment of ubiquitin molecules to lysine residues on target proteins, modulating their stability, localisation or activity.

E3 ubiquitin ligase: Enzyme that recognises substrates and facilitates transfer of ubiquitin from an E2 conjugating enzyme to the target protein.

Deubiquitinase: Enzyme that cleaves ubiquitin chains from substrates, reversing the ubiquitination signal.

NF-κB: Family of transcription factors central to inflammatory gene induction and cell survival, regulated by ubiquitin-dependent pathways.

UFMylation: Ubiquitin-like modification involving UFM1, which regulates ribosome homeostasis and endoplasmic reticulum function.

References

1. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduction and Targeted Therapy (2024).
2. The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons. Nature (2024).
3. Orphan quality control shapes network dynamics and gene expression. Cell (2023).
4. Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches. Molecular Cancer (2024).