Impact of the proteasomal immune adaptation on the early immune response to viral infection
Final Report Abstract
In response to viral infections a cluster of proinflammatory cytokines is secreted, which suppress viral replication and mediate reconstitution of cellular integrity and function. Our data demonstrate that interferon-signalling induces oxidative stress which causes enhanced intracellular accumulation of oxidant-damaged proteins that can be compensated by increased immunoproteasome activity. Interferons stimulate proteasome activity by inducing the formation of immunoproteasomes harbouring the three immunosubunits LMP2, MECL-1 and LMP7. In in vitro approaches we demonstrate that poly-ubiquitin-protein substrates are faster degraded by immunoproteasomes compared to standard proteasomes. Moreover, immunoproteasome-deficiency not only results in accumulation of oxidant-damaged proteins but also causes enhanced apoptosis after interferon stimulation and affects the outcome of EAE-induced inflammation in mice. Thus, immunoproteasomes are essential in the early immune response in order to maintain cellular protein homeostasis upon inflammatory oxidative stress. To extend our data obtained from cytokine stimulation to an infection model, we analyzed alterations of the ubiquitin-proteasome-system during human cytomegalovirus infection. In concordance with our previously observed data, infection of fibroblasts with human cytomegalovirus induced a transient accumulation of oxidant-damaged and ubiquitylated proteins. Detailed analysis of specific viral proteins during infection revealed an enhanced protein oxidation as detected for pp65 immediate early protein. Interestingly, generation of the immunodominant HCMVpp65 epitope was improved by immunoproteasomes and by oxidation and subsequent ubiquitylation of the pp65 protein indicating that oxidation not only causes oxidative stress but also increases generation of major histocompatibility complex class I ligands. Our data suggest a surprising new function of immunoproteasomes, which is at the interface of the innate and the adaptive immune response. The produced radicals affect not only infected cells and proteins derived from pathogens, but also proteins of non-infected cells. In cytokine challenged but non-infected cells i-proteasomes prevent the accumulation of potentially toxic protein aggregates by degradation of oxidant-damaged proteins, thereby preserving cell viability and tissue integrity due to their superior proteolytic capacity. In contrast, infected cells have to signal their infection state to the adaptive immune system by presenting foreign epitopes on MHC class I molecules at the cell surface, a mechanism which is strongly improved by i-proteasome function. These findings point at two different, not each other excluding functions of iproteasomes. As part of the adaptive immune response i-proteasomes increase the peptide supply thereby facilitating antigen presentation, whereas as part of an innate response they fulfill an essential more general role by preserving cell viability through the maintenance of cellular protein homeostasis. Because of the novelty of these findings our data were highlighted by a press release from the Charité and by a “Leading Edge Preview” of Sjoerd van Deventer and Jaques Neefjes in the same issue of Cell.
Publications
-
Remodelling of the ubiquitin-proteasome system in response to interferons. Biochem Soc Trans. 36, 879-84. (2008)
Seifert U, Krüger E
-
Immunoproteasomen:Schutz vor Stress. Biospektrum 06.2010, S.632-634
Krüger E, Seifert U, Kloetzel PM
-
Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142, 613-624. (2010)
Seifert U, Bialy LP, Ebstein F, Bech-Otschir D, Voigt A, Schroter F, Prozorovski T, Lange N, Steffen J, Rieger M, Kuckelkorn U, Aktas O, Kloetzel PM, and Krüger E
-
Redox control of proteasomal function: From molecular mechanisms to functional significance. Antioxid Redox Signal., Feb 12. [Epub ahead of print] (2011)
Kriegenburg, F, Poulsen EG, Koch A, Krüger E, and Hartmann-Petersen R
