- The ubiquitin–proteasome system (UPS) plays a central role in regulating immune cell function by controlling the stability, activity, and turnover of key signalling proteins. Through selective ubiquitination and proteasomal degradation, immune cells rapidly adjust their responses to pathogens, stress, and inflammatory cues. The UPS influences antigen processing, cytokine production, receptor signalling, and immune tolerance, making it indispensable for both innate and adaptive immunity. Its precision and responsiveness position the UPS as a core regulatory mechanism in immune cell biology and host defence.
- The UPS operates through two coordinated components: ubiquitin, a small regulatory protein, and the 26S proteasome, a multi‑subunit protease complex. Immune cell proteins destined for degradation are tagged with ubiquitin through the action of E1, E2, and E3 enzymes. E3 ligases provide substrate specificity, determining which signalling molecules are removed or stabilised. Once polyubiquitinated, proteins are recognised by the proteasome, unfolded, and degraded into peptides. This selective turnover enables immune cells to respond rapidly to external stimuli and maintain tight control over signalling pathways.
- In antigen‑presenting cells, the UPS is essential for generating peptides that bind to MHC class I molecules. Proteasomal degradation produces short peptides that are transported into the endoplasmic reticulum and loaded onto MHC class I complexes. These complexes are then displayed on the cell surface, allowing cytotoxic T cells to recognise infected or abnormal cells. Specialised immune proteasomes, known as immunoproteasomes, enhance the production of peptides with optimal MHC class I binding properties. This adaptation improves antigen presentation during infection and inflammation.
- The UPS also regulates innate immune signalling. In pathways such as NF‑κB, ubiquitination determines whether signalling is activated or terminated. For example, the inhibitor IκB is ubiquitinated and degraded by the proteasome, allowing NF‑κB to enter the nucleus and initiate transcription of inflammatory genes. Conversely, ubiquitination of adaptor proteins such as TRAF6 or MyD88 modulates Toll‑like receptor signalling, shaping cytokine production and inflammatory responses. These regulatory events ensure that innate immunity is both rapid and tightly controlled.
- In adaptive immunity, the UPS influences T‑cell activation, differentiation, and tolerance. Ubiquitination regulates the turnover of T‑cell receptors, co‑stimulatory molecules, and signalling intermediates. E3 ligases such as Cbl and Itch modulate T‑cell responses by targeting activated receptors or transcription factors for degradation. Similarly, UPS‑mediated control of cytokine signalling ensures that T cells differentiate appropriately into effector, regulatory, or memory subsets. In B cells, the UPS regulates receptor editing, antibody production, and survival signals.
- UPS activity is also critical for maintaining immune tolerance. By degrading signalling proteins that promote excessive activation, the UPS prevents autoimmunity and chronic inflammation. Dysregulation of ubiquitination or proteasome function can lead to hyperactive immune responses, contributing to autoimmune diseases such as lupus, rheumatoid arthritis, and multiple sclerosis. Conversely, impaired UPS activity may weaken immune responses, increasing susceptibility to infections.
- UPS dysfunction has significant implications for immune‑related diseases. Viral pathogens often manipulate ubiquitination to evade immune detection, while cancer cells exploit UPS pathways to suppress immune surveillance. Proteasome inhibitors, such as bortezomib, are used clinically to treat multiple myeloma and are being explored for modulating immune responses in other conditions. Emerging technologies like PROTACs offer new ways to selectively degrade immune‑related proteins, opening avenues for targeted immunotherapy.
- Overall, the ubiquitin–proteasome system is a fundamental regulator of immune cell function. Its ability to selectively modify and degrade proteins ensures precise control over antigen presentation, signalling, cytokine production, and immune tolerance. Understanding UPS activity in immune cells provides valuable insight into host defence, inflammation, autoimmunity, and therapeutic innovation.
