Immunoproteasomes Preserve Protein Homeostasis upon Interferon-Induced Oxidative Stress

• Published in: Cell 2010-08, Vol.142 (4), p.613-624
• Main Authors: Seifert, Ulrike, Bialy, Lukasz P., Ebstein, Frédéric, Bech-Otschir, Dawadschargal, Voigt, Antje, Schröter, Friederike, Prozorovski, Timour, Lange, Nicole, Steffen, Janos, Rieger, Melanie, Kuckelkorn, Ulrike, Aktas, Orhan, Kloetzel, Peter-M., Krüger, Elke
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation; CELLBIO; CELLIMMUNO; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Homeostasis; Humans; Inflammation - metabolism; Interferons - immunology; Mice; Mice, Inbred C57BL; Proteasome Endopeptidase Complex - immunology; Proteasome Endopeptidase Complex - metabolism; Proteins - metabolism; Ubiquitination
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2010.07.036

Interferon (IFN)-induced immunoproteasomes (i-proteasomes) have been associated with improved processing of major histocompatibility complex (MHC) class I antigens. Here, we show that i-proteasomes function to protect cell viability under conditions of IFN-induced oxidative stress. IFNs trigger the production of reactive oxygen species, which induce protein oxidation and the formation of nascent, oxidant-damaged proteins. We find that the ubiquitylation machinery is concomitantly upregulated in response to IFNs, functioning to target defective ribosomal products (DRiPs) for degradation by i-proteasomes. i-proteasome-deficiency in cells and in murine inflammation models results in the formation of aggresome-like induced structures and increased sensitivity to apoptosis. Efficient clearance of these aggregates by the enhanced proteolytic activity of the i-proteasome is important for the preservation of cell viability upon IFN-induced oxidative stress. Our findings suggest that rather than having a specific role in the production of class I antigens, i-proteasomes increase the peptide supply for antigen presentation as part of a more general role in the maintenance of protein homeostasis. [Display omitted] ► IFNs trigger ROS production and the formation of oxidant damaged proteins ► i-proteosome-deficient cells accumulate oxidant-damaged proteins ► Enhanced proteolytic activity of the i-proteasome results in efficient clearance of aggregates ► i-proteasomes prevent cellular damage and apoptosis in murine inflammation models