The Function of Immunoproteasomes—An Immunologists’ Perspective

Eshof, Bart L. van den; Medfai, Lobna; Nolfi, Emanuele; Wawrzyniuk, Magdalena; Sijts, Alice J.A.M.

doi:10.3390/cells10123360

Cited by 13 publications

(5 citation statements)

References 105 publications

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“…We previously reported TNFα induces MHCI proteins, including HLA-A, HLA-B and HLA-C , which we observed here too 36 . However, these MHCI complex proteins as well as immunoproteasome ( PSMB8, PSMB9 and PSMB10 ) and immunoproteasome regulator subunits ( PSME1 and PSME2 ), peptide loading proteins ( TAP1 , TAP2 , ERAP1 and ERAP2 ) 37 , 38 and immune checkpoint protein Programmed death- ligand 1 ( CD274 ) were higher induced by IFNγ compared to TNFα. Moreover, IFNγ also induced MHCII complexes required for exogenous antigen presentation.…”

Section: Resultsmentioning

confidence: 98%

Multi-omics delineation of cytokine-induced endothelial inflammatory states

et al. 2023

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Vascular endothelial cells (ECs) form a dynamic interface between blood and tissue and play a crucial role in the progression of vascular inflammation. Here, we aim to dissect the system-wide molecular mechanisms of inflammatory endothelial-cytokine responses. Applying an unbiased cytokine library, we determined that TNFα and IFNγ induced the largest EC response resulting in distinct proteomic inflammatory signatures. Notably, combined TNFα + IFNγ stimulation induced an additional synergetic inflammatory signature. We employed a multi-omics approach to dissect these inflammatory states, combining (phospho-) proteome, transcriptome and secretome and found, depending on the stimulus, a wide-array of altered immune-modulating processes, including complement proteins, MHC complexes and distinct secretory cytokines. Synergy resulted in cooperative activation of transcript induction. This resource describes the intricate molecular mechanisms that are at the basis of endothelial inflammation and supports the adaptive immunomodulatory role of the endothelium in host defense and vascular inflammation.

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Section: Resultsmentioning

confidence: 98%

Multi-omics delineation of cytokine-induced endothelial inflammatory states

et al. 2023

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“…Proteomic profiling additionally unraveled a profound up-regulation of proteasome factors, including proteins crucial for the composition of the immune proteasome (subunits LMP2, LMP7), which is specifically adapted for a role in MHC-class I antigen processing and CD8 + T-cell activation [ 71 ]. By immunohistochemical validation, we identified ß5i/LMP7 immunoreactivity appearing as sarcolemmal aggregation or subsarcolemmal caps, also with co-localization to autophagy proteins such as p62 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy

Holzer,

Uruha,

Roos

et al. 2024

Acta Neuropathol

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Myositis with anti-Ku-autoantibodies is a rare inflammatory myopathy associated with various connective tissue diseases. Histopathological studies have identified inflammatory and necrotizing aspects, but a precise morphological analysis and pathomechanistic disease model are lacking. We therefore aimed to carry out an in-depth morpho-molecular analysis to uncover possible pathomechanisms. Muscle biopsy specimens from 26 patients with anti-Ku-antibodies and unequivocal myositis were analyzed by immunohistochemistry, immunofluorescence, transcriptomics, and proteomics and compared to biopsy specimens of non-disease controls, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Clinical findings and laboratory parameters were evaluated retrospectively and correlated with morphological and molecular features. Patients were mainly female (92%) with a median age of 56.5 years. Isolated myositis and overlap with systemic sclerosis were reported in 31%, respectively. Isolated myositis presented with higher creatine kinase levels and cardiac involvement (83%), whereas systemic sclerosis-overlap patients often had interstitial lung disease (57%). Histopathology showed a wide spectrum from mild to pronounced myositis with diffuse sarcolemmal MHC-class I (100%) and -II (69%) immunoreactivity, myofiber necrosis (88%), endomysial inflammation (85%), thickened capillaries (84%), and vacuoles (60%). Conspicuous sarcoplasmic protein aggregates were p62, BAG3, myotilin, or immunoproteasomal beta5i-positive. Proteomic and transcriptomic analysis identified prominent up-regulation of autophagy, proteasome, and hnRNP-related cell stress. To conclude, Ku + myositis is morphologically characterized by myofiber necrosis, MHC-class I and II positivity, variable endomysial inflammation, and distinct protein aggregation varying from IBM and IMNM, and it can be placed in the spectrum of scleromyositis and overlap myositis. It features characteristic sarcoplasmic protein aggregation on an acquired basis being functionally associated with altered chaperone, proteasome, and autophagy function indicating that Ku + myositis exhibit aspects of an acquired inflammatory protein-aggregate myopathy.

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“…After superimposing the bovine 20S CP into the yeast proteasome crystal structure, it was also proposed that the β7-subunit might mediate Ntn-based proteolytic activity, although this additional activity was not confirmed later on [95]. In vertebrates, interferon-γ induces the synthesis of alternative Ntn-related β-subunits β1i (LMP2), β2i (MECL-1) and β5i (LMP7), hence, resulting in the formation of the so-called immuno-proteasome, which generates peptides that can be further trimmed to efficiently bind into the groove of MHC class I molecules [98]. Finally, a β5t-subunit exclusively expressed in the thymus generates unique peptides that are relevant for T-cell selection [99].…”

Section: Family Of Proteasome Subunits (Pr)mentioning

confidence: 99%

The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives

Linhorst

Lübke

2022

Cells

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N-terminal nucleophile (Ntn)-hydrolases catalyze the cleavage of amide bonds in a variety of macromolecules, including the peptide bond in proteins, the amide bond in N-linked protein glycosylation, and the amide bond linking a fatty acid to sphingosine in complex sphingolipids. Ntn-hydrolases are all sharing two common hallmarks: Firstly, the enzymes are synthesized as inactive precursors that undergo auto-proteolytic self-activation, which, as a consequence, reveals the active site nucleophile at the newly formed N-terminus. Secondly, all Ntn-hydrolases share a structural consistent αββα-fold, notwithstanding the total lack of amino acid sequence homology. In humans, five subclasses of the Ntn-superfamily have been identified so far, comprising relevant members such as the catalytic active subunits of the proteasome or a number of lysosomal hydrolases, which are often associated with lysosomal storage diseases. This review gives an updated overview on the structural, functional, and (patho-)physiological characteristics of human Ntn-hydrolases, in particular.

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The Function of Immunoproteasomes—An Immunologists’ Perspective

Cited by 13 publications

References 105 publications

Multi-omics delineation of cytokine-induced endothelial inflammatory states

Multi-omics delineation of cytokine-induced endothelial inflammatory states

Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy

The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives

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