Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7

Vachharajani, Niyati; Joeris, Thorsten; Luu, Maik; Hartmann, Sabrina; Pautz, Sabine; Jenike, Elena; Pantazis, Georgios; Prinz, Immo; Höfer, Markus; Steinhoff, Ulrich; Visekruna, Alexander

doi:10.18632/oncotarget.14579

Cited by 46 publications

(47 citation statements)

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“…Hence, immunoproteasome inhibition is a promising strategy for reducing IL‐23 secretion and, therefore, suppressing Th17 development. Indeed, in vitro Th17 differentiation was reduced with LU‐005i‐treated T helper cells (Figure ), confirming previous observations, obtained both in vitro and in vivo (Muchamuel et al, ; Schmidt et al, ; Kalim et al, ; Basler et al, ; Vachharajani et al, ). Th17 cells are known to express high levels the multi‐drug transporter MDR1 (also known as P‐glycoprotein and ABCB1), an ATP‐dependent membrane efflux pump with broad substrate specificity (Ramesh et al, ).…”

Section: Discussionsupporting

confidence: 90%

“…Whether the epoxyketone‐peptide proteasome inhibitors, LU‐001i or LU‐005i, are affected by MDR1 remains to be determined. It has been found that inhibiting the immunoproteasome prevents the development of autoimmune diseases and of colitis‐associated cancer (Koerner et al, ; Vachharajani et al, ) in several preclinical animal models (summarized in Basler et al, ). To elucidate the potency of LU‐005i in vivo in an inflammatory disease, we chose to use the DSS‐induced colitis model as a proof of principle.…”

Section: Discussionmentioning

confidence: 99%

“…In haematopoietic cells and in cells stimulated with IFN‐γ or TNF‐α, these proteolytically active subunits are replaced by proteasome subunit beta 9 [β1i; low molecular mass polypeptide (LMP)2], proteasome subunit 10 [β2i; multicatalytic endopeptidase complex‐like (MECL)‐1] and proteasome subunit beta 8 (β5i; LMP7) forming the immunoproteasome (IP). The immunoproteasome is involved in the generation of MHC‐I ligands (Basler et al, ; ; ; ; Kincaid et al, ), in T cell expansion (Basler et al, ; Moebius et al, ), T helper cell differentiation (Muchamuel et al, ; Kalim et al, ; Basler et al, ; Vachharajani et al, ), in protection from immunopathological damage in the brain (Kremer et al, ; Mundt et al, ) and in autoimmune diseases (Muchamuel et al, ; Basler et al, , , ; Zaiss et al, ; Ichikawa et al, ; Nagayama et al, ; Liu et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome

Basler

Maurits

Bruin

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEMulticatalytic endopeptidase complex-like-1 (β2i), low molecular mass polypeptide (LMP) 2 (β1i) and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome, a special type of proteasome mainly expressed in haematopoietic cells. Targeting LMP7 has been shown to be therapeutically effective in preclinical models of autoimmune diseases. In this study, we investigated the selectivity and biological activity of LU-005i, a recently described inhibitor of the immunoproteasome. EXPERIMENTAL APPROACHThe specificity of LU-005i and other immunoproteasome-selective inhibitors was characterized using fluorogenic peptide substrates. The effect of proteasome inhibition on cytokine release was investigated in endotoxin-stimulated mouse splenocytes or human peripheral blood mononuclear cells (PBMCs). The effect of proteasome inhibition on inflammatory bowel disease in the dextran sulfate sodium (DSS)-induced colitis model was assessed by measuring weight loss and colon length. KEY RESULTSLU-005i is the first human and mouse immunoproteasome-selective inhibitor that targets all three proteolytically active immunoproteasome subunits. LU-005i inhibited cytokine secretion from endotoxin-stimulated mouse splenocytes or human PBMCs. Furthermore, differentiation of naïve T helper cells to T helper 17 cells was impaired in the presence of LU-005i. Additionally, LU-005i ameliorated DSS-induced colitis. CONCLUSION AND IMPLICATIONSThis study with a novel pan-immunoproteasome inhibitor substantiates that the immunoproteasome is a promising drug target for the treatment of inflammatory diseases and that exclusive inhibition of LMP7 is not necessary for therapeutic effectiveness. Our results will promote the design of new generations of immunoproteasome inhibitors with optimal therapeutic efficacy for clinical use in the treatment of autoimmunity and cancer.Abbreviations CD, cluster of differentiation; CP, constitutive proteasome; DAI, disease activity index; DSS, dextran sulfate sodium; EAE, experimental autoimmune encephalomyelitis; IP, immunoproteasome; LMP, low molecular mass polypeptide; MECL-1, multicatalytic endopeptidase complex-like-1; MHC, major histocompatibility complex; NEPHGE, non-equilibrium pH gradient gel electrophoresis; PBMCs, peripheral blood mononuclear cells; TCR, T cell receptor; Th, T helper cell; UTY, ubiquitously transcribed tetratricopeptide repeat gene, Y-linked IntroductionThe proteasome is the main protease in charge of generating ligands for major histocompatibility complex (MHC) I presentation (Groettrup et al., 1996;Basler et al., 2009). It has a barrel-shaped structure consisting of four rings, each with seven subunits. The inner two rings consist of β-subunits and bear the catalytically active subunits proteasome subunit beta 6 (β1c), proteasome subunit beta 7 (β2c) and proteasome subunit beta 5 (β5c) (Huber et al., 2012). In haematopoietic cells and in cells stimulated with IFN-γ or TNF-α, these proteolytically active subunits are replaced by proteasome subunit beta...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome

Basler

Maurits

Bruin

et al. 2017

British J Pharmacology

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“…The secretion of different proinflammatory cytokines from LPS‐stimulated human PBMCs or mouse splenocytes as well as TCR‐activated T cells was strongly suppressed by LMP7 inhibition with ONX 0914 . Additionally, ONX 0914 treatment prevented the differentiation of naïve T helper cells to polarized Th17 cells in vitro . Hence, these findings propose the immunoproteasome to be an interesting therapeutic target for the treatment of inflammatory diseases.…”

Section: Introductionmentioning

confidence: 82%

“…Hence, ONX 0914 was used as the prototype LMP7-selective inhibitor in many studies. LMP7 inhibition with ONX 0914, for example, protected from immunopathological damage in the brain after virus infection [4], exacerbated the pathogenesis of experimental systemic Candida albicans infection [5], protected from colitis-associated cancer formation [6,7], and prevented several autoimmune diseases in pre-clinical mouse models [3,[8][9][10][11][12][13][14] (summarized in Ref. [13]).…”

Section: Introductionmentioning

confidence: 99%

Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

et al. 2018

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Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine‐inducible proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL‐1 (β2i), and LMP7 (β5i). Targeting the immunoproteasome in pre‐clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor. Here, we show that PRN1126, developed as an exclusively LMP7‐specific inhibitor, has limited effects on IL‐6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co‐inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU‐001i or ML604440 impairs MHC class I cell surface expression, IL‐6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co‐inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases.

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Immunoproteasome

Kimura¹

2020

Encyclopedia of Life Sciences

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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.

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Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7

Cited by 46 publications

References 40 publications

Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome

Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome

Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

Immunoproteasome

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