Figure 1.

Hypothesis of the masking of epitopes in cell debris by ubiquitin preventing their recognition by the immune system. Eukaryotic cells use autophagy and the ubiquitin–proteasome system (UPS) as their major protein degradation pathways. Whereas the UPS is involved in the rapid degradation of proteins, autophagy pathways can selectively remove protein aggregates, damaged or excess organelles, and pathogens. Ubiquitin have been involved as a specific factor for selective autophagy as exemplified here by autophagy of pathogens. Different cellular adaptors connect pathogens to the protein light chain 3 (LC3), a key autophagy-related protein that is located at the surface of autophagosomes. Proteasome-mediated degradation also requires the ubiquitination of the cargo, which is then recognized by ubiquitin receptors allowing their degradation by the 26S proteasomes. The defective clearance of apoptotic debris by phagocytes and autophagy imbalance can result in the accumulation of cell debris that is responsible for the initiation of systemic autoimmunity. Such defect of clearance induces the release of immunogenic intracellular contents from the dying cells. I hypothesize that ubiquitination protects antigens generated by cells escaping from destruction by the immune system and that failure of ubiquitination mechanisms may induce an immune response to cross-reactive self-antigens that can lead to organ damage.