Molecular Immunology 55 (2013) 106–109 Contents lists available at SciVerse ScienceDirect Molecular Immunology j ourna l ho me pag e: www.elsevier.com/locate/molimm Review Oxidation matters: The ubiquitin proteasome system connects innate immune mechanisms with MHC class I antigen presentation  Annika Warnatsch 1 , Theresa Bergann, Elke Krüger * Charité – Universitätsmedizin Berlin, Charité CrossOver, Institut für Biochemie CCM, Virchowweg 6, 10117 Berlin, Germany a r t i c l e i n f o Article history: Received 30 September 2012 Accepted 8 October 2012 Available online 7 November 2012 Keywords: Antigen presentation MHC class I Virus infection Oxidative stress Immunoproteasome a b s t r a c t During innate immune responses the delicate balance of protein synthesis, quality control and degrada- tion is severely challenged by production of radicals and/or the massive synthesis of pathogen proteins. The regulated degradation of ubiquitin-tagged proteins by the ubiquitin proteasome system (UPS) rep- resents one major pathway for the maintenance of cellular proteostasis and regulatory processes under these conditions. In addition, MHC class I antigen presentation is strictly dependent on an appropri- ate peptide supply by the UPS to efficiently prime CD8 + T cells and to initiate an adaptive immune response. We here discuss recent efforts in defining the link between innate immune mechanisms like cytokine and ROS production, the induction of an efficient adaptive immune response and the specific involvement of the UPS therein. Cytokines and/or infections induce translation and the production of free radicals, which in turn confer oxidative damage to nascent as well as folded proteins. In parallel, the same signaling cascades are able to accelerate the protein turnover by the concomitantly induced ubiqui- tin conjugation and degradation of such damaged polypeptides by immunoproteasomes. The ability of immunoproteasomes to efficiently degrade such oxidant-damaged ubiquitylated proteins protects cells from accumulating toxic ubiquitin-rich aggregates. At the same time, this innate immune mechanism facilitates a sufficient peptide supply for MHC class I antigen presentation and connects it to initiation of adaptive immunity. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction 1.1. The ubiquitin proteasome system The ubiquitin proteasome system (UPS) plays a central role in maintaining the protein homeostasis of cells by the ubiquitin- mediated degradation of short-lived, misfolded, oxidant- or otherwise damaged proteins by the proteasome. This is an essential mechanism for the regulation of numerous important cellular pro- cesses, such as gene transcription, DNA repair, apoptosis, cell cycle regulation, cell differentiation and signaling, as well as the gener- ation of antigenic peptides presented by major histocompatibility (MHC) class I molecules (Goldberg, 2007). The ubiquitylation of protein substrates takes place in a three step enzymatic cascade. The E1 enzyme activates ubiquitin in an ATP-dependent manner and transfers it via a thioester bond on an E2 ubiquitin-conjugating enzyme, which shifts ubiquitin to a substrate-specific E3-ligase. E3-ligases facilitate the covalent  This article belongs to Special Issue on Antigen Processing and Presentation. * Corresponding author. Tel.: +49 30 450528317. E-mail address: elke.krueger@charite.de (E. Krüger). 1 Present address: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA London, UK. modification of substrates with several ubiquitin moieties with a chain link via lysine 48 in the ubiquitin sequence labeling proteins for degradation by the 26S proteasome. The 26S proteasome con- sists of the 20S core complex and at least one regulatory 19S subunit attached to the core end. The 19S subunit recognizes and unfolds poly-ubiquitylated protein substrates prior to their degradation by the 20S core, which represents a barrel-shaped structure consti- tuted of four stacked heptameric rings by the assembly of non- identical  and  subunits ( 1–7  1–7  1–7  1–7 ). Three of -subunits, namely 1, 2 and 5, harbor the active sites of the proteasome conveying caspase-like, trypsin-like and chymotrypsin-like cleav- age specificities, which enables the proteasome to cleave behind almost every residue within a protein (Goldberg, 2007). Apart from the standard proteasome (s-proteasome) different isoforms of the proteasome are described. The appearance of a certain isoform in immune cells and immune tissue led to the des- ignation immunoproteasome (i-proteasome). I-proteasomes are constitutively expressed in immune relevant cells and formed upon exposure to interferons (IFNs) and other cytokines that induce the expression of i-subunits, 1i/Lmp2, 2i/Mecl-1 and 5i/Lmp7. I- subunits replace the catalytically active standard  subunits within the 20S core. Both, s-proteasomes as well as i-proteasomes, are able to produce MHC class I ligands as part of the adaptive immune response. In most instances i-proteasomes generate antigenic 0161-5890/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molimm.2012.10.007