Immunoproteasome subunit deficiency has no influence on the canonical pathway of NF-κB activation

Abstract

a b s t r a c tActivation of the pro-inflammatory transcription factor NF-B requires signal-induced proteasomal degradation of the inhibitor of NF-B (IB) in order to allow nuclear translocation. Most cell types are capable of expressing two types of 20S proteasome core particles, the constitutive proteasome and immunoproteasome. Inducible under inflammatory conditions, the immunoproteasome is mainly characterized through an altered cleavage specificity compared to the constitutive proteasome. However, the question whether immunoproteasome subunits affect NF-B signal transduction differently from constitutive subunits is still up for debate. To study the effect of immunoproteasomes on LPS-or TNF-␣-induced NF-B activation, we used IFN-␥ stimulated peritoneal macrophages and mouse embryonic fibroblasts derived from mice deficient for the immunoproteasome subunits low molecular mass polypeptide (LMP) 2, or LMP7 and multicatalytic endopeptidase complex-like 1 (MECL-1). Along the canonical signaling pathway of NF-B activation no differences in the extent and kinetic of IB degradation were observed. Neither the nuclear translocation and DNA binding of NF-B nor the production of the NF-B dependent cytokines TNF-␣, IL-6, and IL-10 differed between immunoproteasome deficient and proficient cells. Hence, we conclude that immunoproteasome subunits have no specialized function for canonical NF-B activation.

Immunoproteasome in the blood plasma of children with acute appendicitis, and its correlation with proteasome and UCHL1 measured by SPR imaging biosensors

“…Two different types of primary cells prepared from LMP 2-/-, L7M -/-and wildtype mice displayed no differences in the extent and kinetic of IjBa degradation when stimulated with lipopolysaccharide (LPS) or TNF-a. Consistent with this finding, the amount of active NF-jB in the nucleus of knock-out cells as well as the transactivation activity was normal [43].…”

“…IL-1 and TNF-a) and reactive oxygen species, and can lead to the breaking of the blood-brain barrier [21,22,42]. Compared to the constitutive proteasome, immunoproteasomes produce more peptides with a hydrophobic C-terminus, which are well suited for presentation on MHC class I molecules [43]. Mice deficient of any of the immunoproteasome subunits are protected from dextran sulphate sodium-induced colitis [1,43].…”

“…Compared to the constitutive proteasome, immunoproteasomes produce more peptides with a hydrophobic C-terminus, which are well suited for presentation on MHC class I molecules [43]. Mice deficient of any of the immunoproteasome subunits are protected from dextran sulphate sodium-induced colitis [1,43]. The immunoproteasome also has additional immunological functions -immunoproteasome deficiency or inhibition affects T cell survival, expansion and differentiation, cytokine production and progression of autoimmune conditions [1,23,43].…”

“…Mice deficient of any of the immunoproteasome subunits are protected from dextran sulphate sodium-induced colitis [1,43]. The immunoproteasome also has additional immunological functions -immunoproteasome deficiency or inhibition affects T cell survival, expansion and differentiation, cytokine production and progression of autoimmune conditions [1,23,43]. Moreover, mutations in LMP7 and LMP2 in humans cause complex autoimmune and inflammatory phenotypes [39,40].…”

“…The results of the latest study by Bitzer argue clearly against an influence of immunoproteasomes on the canonical pathway of NF-kB activation [43]. Two different types of primary cells prepared from LMP 2-/-, L7M -/-and wildtype mice displayed no differences in the extent and kinetic of IjBa degradation when stimulated with lipopolysaccharide (LPS) or TNF-a.…”