Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress.
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.
Seifert
Ulrike
U
Institut für Biochemie CC2, Charité - Universitätsmedizin Berlin, Oudenarder Strasse 16, D-13347 Berlin, Germany.
Bialy
Lukasz P
LP
Ebstein
Frédéric
F
Bech-Otschir
Dawadschargal
D
Voigt
Antje
A
Schröter
Friederike
F
Prozorovski
Timour
T
Lange
Nicole
N
Steffen
Janos
J
Rieger
Melanie
M
Kuckelkorn
Ulrike
U
Aktas
Orhan
O
Kloetzel
Peter-M
PM
Krüger
Elke
E
D000818:Animals; D017951:Antigen Presentation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007372:Interferons / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D054875:Ubiquitination
D015395:Histocompatibility Antigens Class I; D011506:Proteins; D007372:Interferons; D046988:Proteasome Endopeptidase Complex