The basic principle of adaptive immunity is to strictly discriminate between self and non-self, and a central challenge to overcome is the enormous variety of pathogens that might be encountered. In cell-mediated immunity, immunological discernment takes place at a molecular or cellular level. Central to both mechanisms of discernment is the generation of antigenic peptides associated with MHC class I molecules, which is achieved by a proteolytic complex called the proteasome. To adequately accomplish the discrimination between self and non-self that is essential for adaptive immunity and self-tolerance, two proteasome subtypes have evolved via gene duplication: the immunoproteasome and the thymoproteasome. In this Review, we describe various aspects of these immunity-dedicated proteasomes, from their discovery to recent findings.
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Voges, D., Zwickl, P. & Baumeister, W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu. Rev. Biochem. 68, 1015–1068 (1999).
Collins, G. A. & Goldberg, A. L. The logic of the 26S proteasome. Cell 169, 792–806 (2017).
Arrigo, A.-P., Tanaka, K., Goldberg, A. L. & Welch, W. J. Identity of the 19S ‘prosome’ particle with the large multifunctional protease complex of mammalian cells (the proteasome). Nature 331, 192–194 (1988).
Groll, M. et al. Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 386, 463–471 (1997).
Unno, M. et al. The structure of the mammalian 20S proteasome at 2.75 Å resolution. Structure 10, 609–618 (2002).
Schweitzer, A. et al. Structure of the human 26S proteasome at a resolution of 3.9 Å. Proc. Natl. Acad. Sci. USA 113, 7816–7821 (2016).
da Fonseca, P. C. A., He, J. & Morris, E. P. Molecular model of the human 26S proteasome. Mol. Cell 46, 54–66 (2012).
Chen, S. et al. Structural basis for dynamic regulation of the human 26S proteasome. Proc. Natl. Acad. Sci. USA 113, 12991–12996 (2016).
Lasker, K. et al. Molecular architecture of the 26S proteasome holocomplex determined by an integrative approach. Proc. Natl. Acad. Sci. USA 109, 1380–1387 (2012).
Lander, G. C. et al. Complete subunit architecture of the proteasome regulatory particle. Nature 482, 186–191 (2012).
Bard, J. A. M. et al. Structure and function of the 26S proteasome. Annu. Rev. Biochem. 87, 697–724 (2018).
Huang, X., Luan, B., Wu, J. & Shi, Y. An atomic structure of the human 26S proteasome. Nat. Struct. Mol. Biol. 23, 778–785 (2016).
Kwon, Y. T. & Ciechanover, A. The ubiquitin code in the ubiquitin–proteasome system and autophagy. Trends Biochem. Sci. 42, 873–886 (2017).
Varshavsky, A. The ubiquitin system, an immense realm. Annu. Rev. Biochem. 81, 167–176 (2012).
Blum, J. S., Wearsch, P. A. & Cresswell, P. Pathways of antigen processing. Annu. Rev. Immunol. 31, 443–473 (2013).
Eggensperger, S. & Tampé, R. The transporter associated with antigen processing: a key player in adaptive immunity. Biol. Chem. 396, 1059–1072 (2015).
Martinez, C. K. & Monaco, J. J. Homology of proteasome subunits to a major histocompatibility complex–linked LMP gene. Nature 353, 664–667 (1991).
Rock, K. L. et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78, 761–771 (1994).
Aki, M. et al. Interferon-γ induces different subunit organizations and functional diversity of proteasomes. J. Biochem. 115, 257–269 (1994).
Boes, B. et al. Interferon γ stimulation modulates the proteolytic activity and cleavage site preference of 20S mouse proteasomes. J. Exp. Med. 179, 901–909 (1994).
Driscoll, J., Brown, M. G., Finley, D. & Monaco, J. J. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature 365, 262–264 (1993).
Gaczynska, M., Rock, K. L. & Goldberg, A. L. γ-Interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365, 264–267 (1993).
Akiyama, K. et al. cDNA cloning and interferon γ down-regulation of proteasomal subunits X and Y. Science 265, 1231–1234 (1994).
Hisamatsu, H. et al. Newly identified pair of proteasomal subunits regulated reciprocally by interferon γ. J. Exp. Med. 183, 1807–1816 (1996).
Murata, S. et al. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316, 1349–1353 (2007).
Groettrup, M., Standera, S., Stohwasser, R. & Kloetzel, P. M. The subunits MECL-1 and LMP2 are mutually required for incorporation into the 20S proteasome. Proc. Natl. Acad. Sci. USA 94, 8970–8975 (1997).
Heink, S., Ludwig, D., Kloetzel, P.-M. & Krüger, E. IFN-γ-induced immune adaptation of the proteasome system is an accelerated and transient response. Proc. Natl. Acad. Sci. USA 102, 9241–9246 (2005).
Griffin, T. A. et al. Immunoproteasome assembly: cooperative incorporation of interferon gamma (IFN-γ)-inducible subunits. J. Exp. Med. 187, 97–104 (1998).
Shin, E. C. et al. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J. Clin. Invest. 116, 3006–3014 (2006).
Kniepert, A. & Groettrup, M. The unique functions of tissue-specific proteasomes. Trends Biochem. Sci. 39, 17–24 (2014).
Schmidtke, G., Schregle, R., Alvarez, G., Huber, E. M. & Groettrup, M. The 20S immunoproteasome and constitutive proteasome bind with the same affinity to PA28αβ and equally degrade FAT10. Mol. Immunol. https://doi.org/10.1016/j.molimm.2017.11.030 (2017).
Huber, E. M. & Groll, M. The mammalian proteasome activator PA28 forms an asymmetric α4β3 complex. Structure 25, 1473–1480 (2017).
de Graaf, N. et al. PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I–binding peptides in vivo. Eur. J. Immunol. 41, 926–935 (2011).
Cascio, P. PA28αβ: the enigmatic magic ring of the proteasome? Biomolecules 4, 566–584 (2014).
Huber, E. M. et al. Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell 148, 727–738 (2012).
Guillaume, B. et al. Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules. Proc. Natl. Acad. Sci. USA 107, 18599–18604 (2010).
Ferrington, D. A. & Gregerson, D. S. Immunoproteasomes: structure, function, and antigen presentation. Prog. Mol. Biol. Transl. Sci. 109, 75–112 (2012).
Basler, M., Kirk, C. J. & Groettrup, M. The immunoproteasome in antigen processing and other immunological functions. Curr. Opin. Immunol. 25, 74–80 (2013).
McCarthy, M. K. & Weinberg, J. B. The immunoproteasome and viral infection: a complex regulator of inflammation. Front. Microbiol. 6, 21 (2015).
Kincaid, E. Z. et al. Mice completely lacking immunoproteasomes show major changes in antigen presentation. Nat. Immunol. 13, 129–135 (2011).
Zaiss, D. M. W., de Graaf, N. & Sijts, A. J. A. M. The proteasome immunosubunit multicatalytic endopeptidase complex-like 1 is a T-cell-intrinsic factor influencing homeostatic expansion. Infect. Immun. 76, 1207–1213 (2008).
Moebius, J., van den Broek, M., Groettrup, M. & Basler, M. Immunoproteasomes are essential for survival and expansion of T cells in virus-infected mice. Eur. J. Immunol. 40, 3439–3449 (2010).
Kalim, K. W., Basler, M., Kirk, C. J. & Groettrup, M. Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiation. J. Immunol. 189, 4182–4193 (2012).
Muchamuel, T. et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med. 15, 781–787 (2009).
Li, J. et al. Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation. Kidney Int. 93, 670–680 (2018).
Moritz, K. E. et al. The role of the immunoproteasome in interferon-γ-mediated microglial activation. Sci. Rep. 7, 9365 (2017).
Vachharajani, N. et al. Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7. Oncotarget 8, 50447–50459 (2017).
Koerner, J., Brunner, T. & Groettrup, M. Inhibition and deficiency of the immunoproteasome subunit LMP7 suppress the development and progression of colorectal carcinoma in mice. Oncotarget 8, 50873–50888 (2017).
Althof, N. et al. The immunoproteasome-specific inhibitor ONX 0914 reverses susceptibility to acute viral myocarditis. EMBO Mol. Med. 10, 200–218 (2018).
Ichikawa, H. T. et al. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum. 64, 493–503 (2012).
Basler, M., Dajee, M., Moll, C., Groettrup, M. & Kirk, C. J. Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J. Immunol. 185, 634–641 (2010).
Sula Karreci, E. et al. Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice. Proc. Natl. Acad. Sci. USA 113, E8425–E8432 (2016).
Basler, M. et al. Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome. Br. J. Pharmacol. 175, 38–52 (2018).
Uddin, M. M. et al. Foxn1–β5t transcriptional axis controls CD8+ T-cell production in the thymus. Nat. Commun. 8, 14419 (2017).
Tomaru, U. et al. Exclusive expression of proteasome subunit β5t in the human thymic cortex. Blood 113, 5186–5191 (2009).
Ripen, A. M., Nitta, T., Murata, S., Tanaka, K. & Takahama, Y. Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit β5t. Eur. J. Immunol. 41, 1278–1287 (2011).
Ohigashi, I. et al. Aire-expressing thymic medullary epithelial cells originate from β5t-expressing progenitor cells. Proc. Natl. Acad. Sci. USA 110, 9885–9890 (2013).
Florea, B. I. et al. Activity-based profiling reveals reactivity of the murine thymoproteasome-specific subunit β5t. Chem. Biol. 17, 795–801 (2010).
Ohigashi, I. et al. Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors. Cell Rep. 13, 1432–1443 (2015).
Mayer, C. E. et al. Dynamic spatio-temporal contribution of single β5t+ cortical epithelial precursors to the thymus medulla. Eur. J. Immunol. 46, 846–856 (2016).
Žuklys, S. et al. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat. Immunol. 17, 1206–1215 (2016).
Sasaki, K. et al. Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells. Nat. Commun. 6, 7484 (2015).
Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32, 29–40 (2010).
Xing, Y., Jameson, S. C. & Hogquist, K. A. Thymoproteasome subunit-β5T generates peptide–MHC complexes specialized for positive selection. Proc. Natl. Acad. Sci. USA 110, 6979–6984 (2013).
Takada, K. et al. TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8+ T cells. Nat. Immunol. 16, 1069–1076 (2015).
Rock, K. L. & Goldberg, A. L. Degradation of cell proteins and the generation of MHC class I–presented peptides. Annu. Rev. Immunol. 17, 739–779 (1999).
Murata, S., Takahama, Y. & Tanaka, K. Thymoproteasome: probable role in generating positively selecting peptides. Curr. Opin. Immunol. 20, 192–196 (2008).
Takahama, Y., Tanaka, K. & Murata, S. Modest cortex and promiscuous medulla for thymic repertoire formation. Trends Immunol. 29, 251–255 (2008).
Takahama, Y. et al. Role of thymic cortex-specific self-peptides in positive selection of T cells. Semin. Immunol. 22, 287–293 (2010).
Kincaid, E. Z., Murata, S., Tanaka, K. & Rock, K. L. Specialized proteasome subunits have an essential role in the thymic selection of CD8+ T cells. Nat. Immunol. 17, 938–945 (2016).
Alam, S. M. et al. T-cell-receptor affinity and thymocyte positive selection. Nature 381, 616–620 (1996).
Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).
Flajnik, M. F. & Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11, 47–59 (2010).
Kasahara, M. & Sutoh, Y. Two forms of adaptive immunity in vertebrates: similarities and differences. Adv. Immunol. 122, 59–90 (2014).
Boehm, T. et al. Evolution of alternative adaptive immune systems in vertebrates. Annu. Rev. Immunol. 36, 19–42 (2018).
Boehm, T. et al. VLR-based adaptive immunity. Annu. Rev. Immunol. 30, 203–220 (2012).
Tanaka, K. & Kasahara, M. The MHC class I ligand-generating system : roles of immunoproteasomes and the interferon-γ-inducihle proteasome activator PA28. Immunol. Rev. 163, 161–176 (1998).
Kasahara, M. The 2R hypothesis: an update. Curr. Opin. Immunol. 19, 547–552 (2007).
Kasahara, M., Nakaya, J., Satta, Y. & Takahata, N. Chromosomal duplication and the emergence of the adaptive immune system. Trends Genet. 13, 90–92 (1997).
Kasahara, M. et al. Chromosomal localization of the proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex. Proc. Natl. Acad. Sci. USA 93, 9096–9101 (1996).
Ohta, Y., Goetz, W., Hossain, M. Z., Nonaka, M. & Flajnik, M. F. Ancestral organization of the MHC revealed in the amphibian Xenopus. J. Immunol. 176, 3674–3685 (2006).
Sutoh, Y. et al. Comparative genomic analysis of the proteasome β5t subunit gene: implications for the origin and evolution of thymoproteasomes. Immunogenetics 64, 49–58 (2012).
Kaufman, J. What chickens would tell you about the evolution of antigen processing and presentation. Curr. Opin. Immunol. 34, 35–42 (2015).
Erath, S. & Groettrup, M. No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes. Immunogenetics 67, 51–60 (2015).
Flajnik, M. F. & Kasahara, M. Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15, 351–362 (2001).
Fort, P., Kajava, A. V., Delsuc, F. & Coux, O. Evolution of proteasome regulators in eukaryotes. Genome Biol. Evol. 7, 1363–1379 (2015).
Magor, K. E. et al. Defense genes missing from the flight division. Dev. Comp. Immunol. 41, 377–388 (2013).
Wallny, H.-J. et al. Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens. Proc. Natl. Acad. Sci. USA 103, 1434–1439 (2006).
Chen, C. H., Gobel, T. W. F., Kubota, T. & Cooper, M. D. T cell development in the chicken. Poult. Sci. 73, 1012–1018 (1994).
Kitamura, A. et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J. Clin. Invest. 121, 4150–4160 (2011).
Arima, K. et al. Proteasome assembly defect due to a proteasome subunit β type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo–Nishimura syndrome. Proc. Natl. Acad. Sci. USA 108, 14914–14919 (2011).
Liu, Y. et al. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 64, 895–907 (2012).
Agarwal, A. K. et al. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am. J. Hum. Genet. 87, 866–872 (2010).
Brehm, A. & Krüger, E. Dysfunction in protein clearance by the proteasome: impact on autoinflammatory diseases. Semin. Immunopathol. 37, 323–333 (2015).
McDermott, A., Jacks, J., Kessler, M., Emanuel, P. D. & Gao, L. Proteasome-associated autoinflammatory syndromes: advances in pathogeneses, clinical presentations, diagnosis, and management. Int. J. Dermatol. 54, 121–129 (2015).
Brehm, A. et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J. Clin. Invest. 125, 4196–4211 (2015).
Ohigashi, I. et al. A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production. JCI Insight 2, 93664 (2017).
Nitta, T. et al. Human thymoproteasome variations influence CD8 T cell selection. Sci. Immunol. 2, eaan5165 (2017).
Marx, A. et al. The 2015 World Health Organization Classification of tumors of the thymus: continuity and changes. J. Thorac. Oncol. 10, 1383–1395 (2015).
Yamada, Y. et al. Expression of proteasome subunit β5t in thymic epithelial tumors. Am. J. Surg. Pathol. 35, 1296–1304 (2011).
Yamada, Y. et al. Expression of thymoproteasome subunit β5t in type AB thymoma. J. Clin. Pathol. 67, 276–278 (2014).
Tanaka, K. Role of proteasomes modified by interferon-γ in antigen processing. J. Leukoc. Biol. 56, 571–575 (1994).
Magarian Blander, J. Regulation of the cell biology of antigen cross-presentation. Annu. Rev. Immunol. 36, 717–753 (2018).
Palmowski, M. J. et al. Role of immunoproteasomes in cross-presentation. J. Immunol. 177, 983–990 (2006).
Vigneron, N. & Van den Eynde, B. J. Insights into the processing of MHC class I ligands gained from the study of human tumor epitopes. Cell. Mol. Life Sci. 68, 1503–1520 (2011).
Granados, D. P., Laumont, C. M., Thibault, P. & Perreault, C. The nature of self for T cells—a systems-level perspective. Curr. Opin. Immunol. 34, 1–8 (2015).
Starck, S. R. & Shastri, N. Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunol. Rev. 272, 8–16 (2016).
Yewdell, J. W. DRiPs solidify: progress in understanding endogenous MHC class I antigen processing. Trends Immunol. 32, 548–558 (2011).
Wei, J. & Yewdell, J. W. Immunoribosomes: where’s there’s fire, there’s fire. Mol. Immunol. https://doi.org/10.1016/j.molimm.2017.12.026 (2018).
Rock, K. L., Farfán-Arribas, D. J., Colbert, J. D. & Goldberg, A. L. Re-examining class-I presentation and the DRiP hypothesis. Trends Immunol. 35, 144–152 (2014).
Vigneron, N., Ferrari, V., Stroobant, V., Abi Habib, J. & Van den Eynde, B. J. Peptide splicing by the proteasome. J. Biol. Chem. 292, 21170–21179 (2017).
Mishto, M. & Liepe, J. Post-translational peptide splicing and T cell responses. Trends Immunol. 38, 904–915 (2017).
Liepe, J. et al. A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 354, 354–358 (2016).
Dalet, A., Stroobant, V., Vigneron, N. & Van den Eynde, B. J. Differences in the production of spliced antigenic peptides by the standard proteasome and the immunoproteasome. Eur. J. Immunol. 41, 39–46 (2011).
Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).
Kasahara, M. Genome duplication and T cell immunity. Prog. Mol. Biol. Transl. Sci. 92, 7–36 (2010).
Śledź, P. & Baumeister, W. Structure-driven developments of 26S proteasome inhibitors. Annu. Rev. Pharmacol. Toxicol. 56, 191–209 (2016).
Santos, R. L. A. et al. Structure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated lymphocytes. Nat. Commun. 8, 1692 (2017).
Richy, N. et al. Structure-based design of human immuno- and constitutive proteasomes inhibitors. Eur. J. Med. Chem. 145, 570–587 (2018).
Tanahashi, N. et al. Hybrid proteasomes. Induction by interferon-γ and contribution to ATP-dependent proteolysis. J. Biol. Chem. 275, 14336–14345 (2000).
Murata, S., Yashiroda, H. & Tanaka, K. Molecular mechanisms of proteasome assembly. Nat. Rev. Mol. Cell Biol. 10, 104–115 (2009).
Blair, J. E. & Hedges, S. B. Molecular phylogeny and divergence times of deuterostome animals. Mol. Biol. Evol. 22, 2275–2284 (2005).
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Murata, S., Takahama, Y., Kasahara, M. et al. The immunoproteasome and thymoproteasome: functions, evolution and human disease. Nat Immunol 19, 923–931 (2018). https://doi.org/10.1038/s41590-018-0186-z
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