HECT ubiquitin ligases as regulators of inflammatory signalling

Ubiquitination is a versatile post-translational modification that regulates protein stability, localisation and signalling. By modifying a wide range of substrates, ubiquitination controls key physiological processes, including inflammatory responses, which are the focus of this article. Precise regulation of inflammatory signalling is essential, as insufficient activation compromises host defence while sustained signalling contributes to chronic inflammation, autoimmunity and degenerative disease. Within the ubiquitin system, E3 ligases confer substrate specificity and influence ubiquitin chain topology, thereby directing downstream protein fate and signalling outcomes. HECT family E3 ligases form transient E3~ubiquitin thioester intermediates that enable controlled ubiquitin transfer to target proteins. Through this activity, they regulate the strength and duration of inflammatory signalling pathways. In this review, we discuss HECT E3 ubiquitin ligases involved in inflammation and how their ubiquitin-modifying functions influence immune signalling and inflammatory disease progression.