The proteasome - victim or culprit in autoimmunity

•In proteasome-associated autoinflammatory syndromes (PRAAS) disease causing mutations result in reduced proteasome activity.•Several studies have shown an up-regulation of inducible subunits of the proteasome in systemic autoimmune diseases.•Proteasome inhibition was shown to be efficacious in several in-vitro studies and animal models of autoimmune diseases.•A number of available proteasome inhibitors has been characterized as potent immune-suppressants.•Promising application of proteasome inhibitors in autoimmune diseases should be confirmed in controlled clinical trials.

The ubiquitin proteasome system is closely connected to apoptosis, autophagy, signaling of inflammatory cytokines and generation of ligands for MHC class I antigen presentation. Proteasome function in the innate immune response becomes particularly evident in patients with proteasome-associated autoinflammatory syndromes (PRAAS), where disease causing mutations result in reduced proteasome activity. PRAAS can be classified as a novel type of interferonopathy, however the molecular mechanism and signaling pathways leading from impaired proteasome capacity, the accumulation of damaged proteins, and the induction of type I IFN-genes remain to be determined. In contrast, several studies have confirmed an up-regulation of inducible subunits of the proteasome in systemic autoimmune diseases. Since proteasome inhibition was shown to be efficacious in several in-vitro studies and animal models of autoimmune diseases, it is justified to investigate the application of proteasome inhibitors in human disease. In this context, a number of available proteasome inhibitors has been characterized as potent immune-suppressants. The mode of action of proteasome inhibition interferes with the quality control of the huge amounts of synthetized antibodies causing an unfolded protein response. Further effects of proteasome inhibition includes inhibition of NFκB activation as well as direct activation of intrinsic and extrinsic pathways of apoptosis. The preliminary clinical work on proteasome inhibition in autoimmune diseases comprises only few studies in small cohorts with promising effects, which needs to be confirmed in controlled clinical trials.