Adaptation of proteasome composition in inflammatory response - the impact of the hybridproteasome

• Applicant: Professorin Dr. Antje Beling, since 3/2017
• Subject Area: Immunology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234637411

The ubiquitin-proteasome-system (UPS) is vital for cells to preserve the intracellular balance of protein synthesis and destruction. By degrading short-lived poly-ubiquitin-tagged proteins it also determines the availability of regulatory proteins and controls a large number of cellular processes. The UPS is responsible for the generation of the vast majority of virus derived peptides presented by MHC class I molecules at the cell surface. This function is generally aided by cytokine-induced synthesis of the alternative catalytic subunits beta1i/LMP2, betai/MECL1, beta5i/LMP7 giving rise to the de novo formation of so-called immunoproteasomes (i-proteasomes). Cytokine signaling in inflammation contributes to innate immune response mechanisms against invading pathogens. In infected tissues, pro-inflammatory cytokines also recruit cells of the immune system that invade into the infected organ. Contrary, by producing radicals cytokines simultaneously confer severe stress in cells. These radicals affect infected cells, but at the same time also proteins from non-infected cells that are also exposed to cytokines. In non-infected cytokine exposed cells or tissues, i-proteasomes preserve cell viability and tissue integrity by efficiently degrading oxidant-damaged poly-ubiquitylated proteins, thereby preventing the accumulation of potentially toxic protein aggregates. At the same time, infected cells must rapidly signal their infectious state to the adaptive immune system by presenting epitopes on MHC class I molecules at the cell surface, a mechanism that is strongly improved by i-proteasome function. These two non-excluding functions locate i-proteasomes with their superior proteolytic capacity at the crossroad of the innate and the adaptive immune response. The role of the IFN-inducible proteasome activator PA28, which is simultaneously up-regulated with the i-proteasome upon cytokine signaling and which interacts with i-proteasomes to form the so-called hybridproteasome (i-proteasome - PA28), is in this context still unresolved. This proposal aims to elucidate the function of the hybridproteasome and thus the general adaptation of the UPS in inflammation. Making use of a hybridproteasome-deficient mouse model, here we aim to investigate the impact of hybridproteasome function in different inflammatory conditions. To address these issues in vivo we will take advantage of the LPS-induced hepatitis and the Coxsackievirus B3-induced myocarditis model. We hypothesize that as a response of hybridproteasome activity UPS adaptation in inflammation facilitates degradation of accumulating oxidant-damaged proteins and this way protects from cellular injury in inflammation.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Professorin Dr. Elke Beate Krüger, until 2/2017