Immunoproteasome

Abstract

The immunoproteasome is a proteolytic complex whose five subunits, β1i, β2i, β5i, PA28α and PA28β, are replaced with subunits in the constitutive proteasome. It plays an important role in the immune system and the pathogenesis of inflammatory diseases. In addition, the immunoproteasome regulates the polarisation of immune cells such as M2 macrophages and Th1 and Th17 lymphocytes. While expression of the immunoproteasome is dominant in haematopoietic cells, nonhaematopoietic cells in various peripheral tissues also express the immunoproteasome, and its expression is enhanced by inflammatory cytokines and stress signals. Recent studies indicate that each subunit of the immunoproteasome plays a unique role in nonhaematopoietic cells. For instance, β5i plays a critical role in adipogenesis and metabolic disorders. Furthermore, genetical mutation of the immunoproteasome subunits causes autoinflammatory diseases and lipodystrophy.

Key Concepts

  • The immunoproteasome plays an important role in the immune system.
  • The immunoproteasome is involved in the pathogenesis of inflammatory diseases.
  • Inhibition of the immunoproteasome is useful as a treatment for inflammatory diseases and tumours.
  • The immunoproteasome plays a unique role in nonhaematopoietic cells.
  • Deficiency of the immunoproteasome influences endocrine metabolic functions.
  • Mutation of the immunoproteasome subunit is associated with autoinflammatory diseases and lipodystrophy.

Keywords: immunoproteasome; β1i; β2i; β5i; inflammatory diseases; roles in nonhaematopoietic cells

Figure 1. Structures of the proteasomes. The proteasomes have a core and two regulators. The core is composed of four rings: two α‐rings and two β‐rings. The β‐ring is composed of seven proteins and three of them (β1, β2 and β5) have enzymatic activities. These three proteins are replaced with β1i, β2i and β5i in the immunoproteasome, and β1i, β2i and β5t in the thymoproteasome. Both the immunoproteasome and the thymoproteasome have 11S regulators (PA28α and PA28β) instead of 19S regulators.
Figure 2. Deficiency of β5i in haematopoietic cells. Th17 cell numbers increase in autoimmune conditions, and deficiency of β5i decreases their population. Both M1 and M2 macrophages are present during inflammatory conditions, and deficiency of β5i increases the population of M2 cells. These changes in the expression of β5i may help suppressing inflammatory conditions.
Figure 3. Cell differentiation and function are influenced by a deficiency in or inhibition of the immunoproteasome subunits. Deficiency and inhibition of β5i suppress the differentiation of preadipocytes and myoblasts. The deficiency of β5i suppresses leptin production and increases adiponectin expression from adipocytes. The deficiency of β1i restores hypothyroidism and disrupted thyroid architecture in a mouse model of Hashimoto thyroiditis.
Figure 4. Mutations in the human PSMB8 (β5i, LMP7) related to PRAAS1. Mutations in the proteasome‐associated autoinflammatory syndrome (PRAAS) are displayed in both the E1 and E2 isoforms of PSMB8.
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Further Reading

Basler M, Mundt S, Bitzer A, Schmidt C and Groettrup M (2015) The immunoproteasome: a novel drug target for autoimmune diseases. Clinical and Experimental Rheumatology 33 (Supple. 92): S74–S79.

Kimura H, Caturegli P, Takahashi M and Suzuki K (2015) New insights into the function of the immunoproteasome in immune and nonimmune cells. Journal of Immunology Research 2015: 541984.

Morozov AV and Karpov VL (2019) Proteasomes and several aspects of their heterogeneity relevant to cancer. Frontiers in Oncology 9: 761.

Pickering AM, Lehr M and Miller RA (2015) Life span of mice and primates correlates with immunoproteasome expression. Journal of Clinical Investigation 125: 2059–2068.

Yasutomo K (2019) Dysregulation of immunoproteasomes in autoinflammatory syndromes. International Immunology 31: 631–637.

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Kimura, Hiroaki(May 2020) Immunoproteasome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026244]