Proteasome Inhibitors as Therapeutics of Autoimmune Diseases
The ubiquitin-proteasome system (UPS) plays a central role in maintaining cellular homeostasis by controlling the timely breakdown of many key proteins, including those involved in cell cycle regulation, activation of transcription factors (for example, NF-κB) and apoptosis induction (Figure 1A,B). The proteasome has a 26S structure, which consists of the 19S regulator and the 20S central proteolytic core (Figure 2A). Three β-subunits within the 20S core of the proteasome harbor its catalytic activity: the β5 subunit (PSMB5, chymotrypsin-like activity), the β1 subunit (PSMB6, caspase-like activity) and the β2 subunit (PSMB7, trypsin-like activity). Upon stimulation by pro-inflammatory stimuli, for example interferon (IFN)-γ or TNFα, these constitutive proteasome subunits can be replaced by immunoproteasome subunits β5i (PSMB8, LMP7), β1i (PSMB9, LMP2) and β2i (PSMB10, MECL1) and to assemble immunoproteasomes, along with PA28 as regulatory cap (Figure 2B). Immunoproteasomes are mainly found in cells of hematological origin in which they convey specialized functions, including: a) facilitating endogenous antigen presentation via major histocompatibility complex (MHC) class I; b) splicing of antigenic peptides and cross-presentation of exogenous antigens via MHC class I on DCs; and c) preserving protein homeostasis after IFN-γ-induced oxidative stress. Beyond this, hybrid variants of immunoproteasomes with constitutive subunits also have been identified in murine heart tissue as well as in human liver, colon, small intestine, kidneys, tumor cells and DCs. These hybrid forms displayed unique antigen-processing properties, thereby expanding the repertoire of antigen presentation by specific cells. Apart from constitutive proteasomes and immunoproteasomes, a third proteasome variant, designated thymo-proteasomes, was identified in cortical thymic epithelial cells. Their function seems to be required for positive selection of CD8+ T cells and in the control of cytokine release.
(Enlarge Image)
Figure 1.
Role of proteasomes in protein degradation and nuclear factor-κ B activation. (A) After initial synthesis, proteins at the end of their (functional) life-span, or damaged/misfolded proteins, are subject to degradation after conjugating with an ubiquitin (Ub) tag. Recognition by the proteasome initiates protein degradation to smaller peptides, which are further processed by aminopeptidases either to free amino acid for renewed protein synthesis or to trimmed peptides presented by major histocompatibility complex class I molecules. (B) Mechanism of blockade of nuclear factor (NF)-κB activation by the proteasome inhibitor bortezomib. This inhibitory effect prevents the degradation of the natural inhibitor of NF-κB (that is, IκB) along with nuclear translocation of p50/p65 and transcription of pro-inflammatory cytokines. IL, interleukin; TNF, tumor necrosis factor.
(Enlarge Image)
Figure 2.
Subunit composition of constitutive and immunoproteasomes. (A) 20S core proteasome. (B) Fully assembled proteasome. Coloured subunits represent catalytic subunits. IFN, interferon; TNF, tumor necrosis factor.
Proteasome Subtypes
The ubiquitin-proteasome system (UPS) plays a central role in maintaining cellular homeostasis by controlling the timely breakdown of many key proteins, including those involved in cell cycle regulation, activation of transcription factors (for example, NF-κB) and apoptosis induction (Figure 1A,B). The proteasome has a 26S structure, which consists of the 19S regulator and the 20S central proteolytic core (Figure 2A). Three β-subunits within the 20S core of the proteasome harbor its catalytic activity: the β5 subunit (PSMB5, chymotrypsin-like activity), the β1 subunit (PSMB6, caspase-like activity) and the β2 subunit (PSMB7, trypsin-like activity). Upon stimulation by pro-inflammatory stimuli, for example interferon (IFN)-γ or TNFα, these constitutive proteasome subunits can be replaced by immunoproteasome subunits β5i (PSMB8, LMP7), β1i (PSMB9, LMP2) and β2i (PSMB10, MECL1) and to assemble immunoproteasomes, along with PA28 as regulatory cap (Figure 2B). Immunoproteasomes are mainly found in cells of hematological origin in which they convey specialized functions, including: a) facilitating endogenous antigen presentation via major histocompatibility complex (MHC) class I; b) splicing of antigenic peptides and cross-presentation of exogenous antigens via MHC class I on DCs; and c) preserving protein homeostasis after IFN-γ-induced oxidative stress. Beyond this, hybrid variants of immunoproteasomes with constitutive subunits also have been identified in murine heart tissue as well as in human liver, colon, small intestine, kidneys, tumor cells and DCs. These hybrid forms displayed unique antigen-processing properties, thereby expanding the repertoire of antigen presentation by specific cells. Apart from constitutive proteasomes and immunoproteasomes, a third proteasome variant, designated thymo-proteasomes, was identified in cortical thymic epithelial cells. Their function seems to be required for positive selection of CD8+ T cells and in the control of cytokine release.
(Enlarge Image)
Figure 1.
Role of proteasomes in protein degradation and nuclear factor-κ B activation. (A) After initial synthesis, proteins at the end of their (functional) life-span, or damaged/misfolded proteins, are subject to degradation after conjugating with an ubiquitin (Ub) tag. Recognition by the proteasome initiates protein degradation to smaller peptides, which are further processed by aminopeptidases either to free amino acid for renewed protein synthesis or to trimmed peptides presented by major histocompatibility complex class I molecules. (B) Mechanism of blockade of nuclear factor (NF)-κB activation by the proteasome inhibitor bortezomib. This inhibitory effect prevents the degradation of the natural inhibitor of NF-κB (that is, IκB) along with nuclear translocation of p50/p65 and transcription of pro-inflammatory cytokines. IL, interleukin; TNF, tumor necrosis factor.
(Enlarge Image)
Figure 2.
Subunit composition of constitutive and immunoproteasomes. (A) 20S core proteasome. (B) Fully assembled proteasome. Coloured subunits represent catalytic subunits. IFN, interferon; TNF, tumor necrosis factor.
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