Does antigen masking by ubiquitin chains protect from the development of autoimmune diseases?

Abstract

Autoimmune diseases are characterized by the production of antibodies against self-antigens and generally arise from a failure of central or peripheral tolerance. However, these diseases may develop when newly appearing antigens are not recognized as self by the immune system. The mechanism by which some antigens are "invisible" to the immune system is not completely understood. Apoptotic and complement system defects or autophagy imbalance can generate this antigenic autoreactivity. Under particular circumstances, cellular debris containing autoreactive antigens can be recognized by innate immune receptors or other sensors and can eventually lead to autoimmunity. Ubiquitination may be one of the mechanisms protecting autoreactive antigens from the immune system that, if disrupted, can lead to autoimmunity. Ubiquitination is an essential post-translational modification used by cells to target proteins for degradation or to regulate other intracellular processes. The level of ubiquitination is regulated during T cell tolerance and apoptosis and E3 ligases have emerged as a crucial signaling pathway for the regulation of T cell tolerance toward self-antigens. I propose here that an unrecognized role of ubiquitin and ubiquitin-like proteins could be to render intracellular or foreign antigens (present in cellular debris resulting from apoptosis, complement system, or autophagy defects) invisible to the immune system in order to prevent the development of autoimmunity.

Keywords: UBLs; apoptosis; autoimmunity; autophagy; immune tolerance; ubiquitin.

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.