Emerging roles of immunoproteasomes beyond MHC class I antigen processing

Abstract

The proteasome is a multi-catalytic protein complex whose primary function is the degradation of abnormal or foreign proteins. Upon exposure of cells to interferons (IFNs), the β1i/LMP2, β2i/MECL-1, and β5i/LMP7 subunits are induced and incorporated into newly synthesized immunoproteasomes (IP), which are thought to function solely as critical players in the optimization of the CD8(+) T-cell response. However, the observation that IP are present in several non-immune tissues under normal conditions and/or following pathological events militates against the view that its role is limited to MHC class I presentation. In support of this concept, the recent use of genetic models deficient for β1i/LMP2, β2i/MECL-1, or β5i/LMP7 has uncovered unanticipated functions for IP in innate immunity and non-immune processes. Herein, we review recent data in an attempt to clarify the role of IP beyond MHC class I epitope presentation with emphasis on its involvement in the regulation of protein homeostasis, cell proliferation, and cytokine gene expression.

Fig. 1

Immune and non-immune functions of the incorporated β1i/LMP2, β5i/LMP7, and β2i/MECL-1 inducible subunits. The proteasomal degradation of misfolded proteins (DRiPs) as well as regulator factors involved in cell cycle and cell signaling is a permanent ongoing process. The SP is less efficient than the IP at eliminating poly-ubiquitylated substrates and its capacity can be overloaded, thereby resulting in the accumulation of harmful protein aggregates (ALIS). The constitutive presence of IP (or its formation in response to IFN-γ) is accompanied by an acceleration of the degradation rate of all poly-ubiquitylated proteins which restores (or preserves) protein homeostasis. The increased protein turnover is not limited to DRiPs but also deals with other poly-ubiquitylated proteins including IκBα, p53 and/or p21 cip1/WAF1 whose increased degradation rate has impacts on cell cycle regulation and cytokine gene expression