A latest study published in Nature reveals a previously unrecognized role for proteasomes in innate immunity, demonstrating how proteasome-derived defence peptides (PDDPs) serve as a first line of defence against bacterial infections. This study challenges the long-standing notion that proteasomes primarily function in antigen presentation, uncovering their crucial role in direct bacterial defence.
Unveiling Proteasome-Derived Defence Peptides (PDDPs)
For decades, proteasomes have been known for their role in antigen processing and major histocompatibility complex (MHC) class I presentation. However, researchers have now discovered that proteasomal degradation also generates antimicrobial peptides that directly impede bacterial growth. These PDDPs disrupt bacterial membranes and act both constitutively and in response to infection. This marks a significant paradigm shift in our understanding of cellular immunity.
Using in silico predictions, researchers identified hundreds of thousands of cationic peptides generated by proteasomal cleavage. These peptides exhibit antimicrobial properties and contribute to an autonomous immune response, highlighting the proteasome as a crucial player in cellular defence mechanisms.
Dynamic Proteasome Adaptation to Infection
Upon bacterial infection, proteasomes undergo compositional and functional changes that enhance their antimicrobial activity. The study found that PSME3, a proteasome activator, is recruited during infection, increasing tryptic-like cleavage and boosting the production of PDDPs. Interestingly, PSME3 deficiency has been linked to increased susceptibility to sepsis and fungal infections, further underscoring its importance in immune regulation.
A New Model: Proteolysis-Driven Immunity
This discovery positions proteasomes at the intersection of innate and adaptive immunity, proposing a new model termed proteolysis-driven immunity. This dual-function mechanism ensures immune protection through both antigen processing for adaptive responses and direct bacterial killing via PDDPs. Evolutionary analysis suggests that proteasomes may have initially evolved as antimicrobial agents before their role in antigen presentation emerged, reinforcing their significance as an evolutionary cornerstone of immune defence.
Implications for Medicine and Biotechnology
The identification of PDDPs opens new avenues for antibiotic development, particularly in the fight against antibiotic-resistant bacteria. Unlike conventional antibiotics, these endogenous peptides may offer immune tolerance benefits, reducing adverse reactions often associated with synthetic antimicrobials. The study’s findings suggest that harnessing proteasome-derived peptides could lead to innovative therapies for infectious diseases and immunocompromised conditions.
One particularly potent PDDP, derived from a serine/threonine phosphatase, was found to effectively kill bacteria such as Pseudomonas and E. coli. In mouse models, it provided protection against sepsis comparable to conventional antibiotics, emphasizing its therapeutic potential.
Future Directions
While this study uncovers an essential function of proteasomes in innate immunity, several critical questions remain. Researchers aim to further explore how PDDPs are secreted, how different immune and non-immune cells utilize these peptides, and whether they act synergistically, akin to Toll-like receptor (TLR)-activated antimicrobial peptides. Additionally, understanding the regulation of PSME3 recruitment could provide deeper insights into the dynamic interplay between proteasomes and immune responses.
Conclusion
This pioneering study transforms our understanding of cellular immunity, revealing proteasomes as integral to both innate and adaptive defence. By identifying proteasome-derived defence peptides as natural antibiotics, researchers have unveiled an untapped resource with vast therapeutic potential. As we continue to explore the role of proteasomes in immunity, these findings pave the way for novel antimicrobial strategies, offering hope in the battle against drug-resistant pathogens.
