Proteasome function shapes innate and adaptive immune responses

Abstract

The proteasome system degrades more than 80% of intracellular proteins into small peptides. Accordingly, the proteasome is involved in many essential cellular functions, such as protein quality control, transcription, immune responses, cell signaling, and apoptosis. Moreover, degradation products are loaded onto major histocompatibility class I molecules to communicate the intracellular protein composition to the immune system. The standard 20S proteasome core complex contains three distinct catalytic active sites that are exchanged upon stimulation with inflammatory cytokines to form the so-called immunoproteasome. Immunoproteasomes are constitutively expressed in immune cells and have different proteolytic activities compared with standard proteasomes. They are rapidly induced in parenchymal cells upon intracellular pathogen infection and are crucial for priming effective CD8(+) T-cell-mediated immune responses against infected cells. Beyond shaping these adaptive immune reactions, immunoproteasomes also regulate the function of immune cells by degradation of inflammatory and immune mediators. Accordingly, they emerge as novel regulators of innate immune responses. The recently unraveled impairment of immunoproteasome function by environmental challenges and by genetic variations of immunoproteasome genes might represent a currently underestimated risk factor for the development and progression of lung diseases. In particular, immunoproteasome dysfunction will dampen resolution of infections, thereby promoting exacerbations, may foster autoimmunity in chronic lung diseases, and possibly contributes to immune evasion of tumor cells. Novel pharmacological tools, such as site-specific inhibitors of the immunoproteasome, as well as activity-based probes, however, hold promises as innovative therapeutic drugs for respiratory diseases and biomarker profiling, respectively.

Proteasome Structure and Assembly

“…The propeptides of the individual immunosubunits help drive their selective incorporation specifically into immunoproteasomes [55,56]. Most immunoproteasomes bear all three βi subunits in each β ring, but some are assembled as mixed proteasomes containing both constitutive β and βi subunits[57]. This implies some flexibility in the order of subunit addition during proteasome assembly.…”

Differential gene expression analysis of symbiotic and aposymbiotic Exaiptasia anemones under immune challenge with Vibrio coralliilyticus

“…Chemokine pathway had three highly DE genessignal transducer and activator of transcription 1-alpha/beta (STAT1) was up-regulated while C-X-C chemokine receptor type 4 (CXCR4), and guanine nucleotide-binding protein subunit beta-4 (GBB4) were Two antigen processing genes were highly DE; proteasome activator subunit 2 (PSME2/PA28 beta) was up-regulated for Vibrio, and regulator factor X-associated ankyrin-containing protein (RFXK) was down-regulated for aposymbiosis. Proteasomes are involved in antigen processing (Michalek, Grant, Gramm, Goldberg, & Rock, 1993) and degradation of other intracellular proteins (Tanaka, 2009), including cytotoxic damaged proteins resulting from the oxidative stress of an immune response (Kammerl & Meiners, 2016). Traylor-Knowles, Rose, Sheets, and Palumbi (2017) observed up-regulation of proteasome components in Acropora hyacinthus exposed to heat stress.…”

Diminished nuclear RNA decay upon Salmonella infection upregulates antibacterial noncoding RNA s

“…Pathogenic infection activates caspase‐1, a protease that regulates the processing and secretion of interleukin‐1 family members (Ogura et al , ). Additionally, the proteasome is activated by infection (Kammerl & Meiners, ). However, our investigation into the presumed proteolysis of MTR4 and RRP6, using inhibitors of the proteasome (MG‐132) and caspase‐1 (V‐zVAD‐fmk), respectively, did not explain this response to Salmonella infection (data not shown).…”