Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

Karreci, Esilida Sula; Fan, Hao; Uehara, Mayuko; Mihali, Albana B; Singh, Pradeep K.; Kurdi, Ahmed T.; Solhjou, Zhabiz; Riella, Leonardo V.; Ghobrial, Irène M.; Laragione, Teresina; Routray, Sujit; Assaker, Jean Pierre; Wang, Rong; Sukenick, George; Shi, Lei; Barrat, Franck J.; Nathan, Carl; Lin, Gang; Azzi, Jamil

doi:10.1073/pnas.1618548114

Cited by 59 publications

(83 citation statements)

References 32 publications

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“…36 Ac-ANW-AMC hydrolysis by proteasomes isolated from healthy donor BMPCs was low but was significantly increased in proteasomes isolated from HLA-sensitized patient CD138 + BMPCs ( Figure 4E). Ac-ANW-AMC is a fluorogenic substrate preferentially cleaved by i20S proteasomes and is not hydrolyzed by c20s proteasomes.…”

Section: I20s Proteasome Activity Is Increased In Bmpcs Upon In Vivmentioning

confidence: 98%

“…Therefore, we also is not hydrolyzed by c20s proteasomes. 36 Ac-ANW-AMC hydrolysis by proteasomes isolated from healthy donor BMPCs was low but was significantly increased in proteasomes isolated from HLA-sensitized patient CD138 + BMPCs ( Figure 4E). Ac-ANW-AMC hydrolysis by proteasomes from BMPCs of carfilzomib-treated HLA-sensitized patients was even greater.…”

Section: I20s Proteasome Activity Is Increased In Bmpcs Upon In Vivmentioning

confidence: 98%

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Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

Woodle

Tremblay

Brailey³

et al. 2020

American Journal of Transplantation

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Donor-specific antibodies (DSAs) have a deleterious effect on allografts and remain a major immunologic barrier in transplantation. Current therapies to eliminate DSAs are ineffective in highly HLA-sensitized patients. Proteasome inhibitors have been employed as a strategy to target bone marrow plasma cells (BMPCs), the source of long-term antibody production; however, their efficacy has been limited by poorly defined drug-resistance mechanisms. Here, we performed transcriptomic profiling of CD138 + BMPCs that survived in vivo desensitization therapy with the proteasome inhibitor carfilzomib to identify mechanisms of drug resistance. The results revealed a genomic signature that included increased expression of the immunoproteasome, a highly specialized proteasomal variant. Western blotting and functional studies demonstrated that catalytically active immunoproteasomes and the immunoproteasome activator PA28 were upregulated in carfilzomib-resistant BMPCs.Carfilzomib-resistant BMPCs displayed reduced sensitivity to the proteasome inhibitors carfilzomib, bortezomib, and ixazomib, but enhanced sensitivity to an immunoproteasome-specific inhibitor ONX-0914. Finally, in vitro carfilzomib treatment of BMPCs from HLA-sensitized patients increased levels of the immunoproteasome β5i (PSMB8) catalytic subunit suggesting that carfilzomib therapy directly induces an adaptive immunoproteasome response. Taken together, our results indicate that carfilzomib induces structural changes in proteasomes and immunoproteasome formation. K E Y W O R D Sbasic (laboratory)

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Section: I20s Proteasome Activity Is Increased In Bmpcs Upon In Vivmentioning

confidence: 98%

Section: I20s Proteasome Activity Is Increased In Bmpcs Upon In Vivmentioning

confidence: 98%

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

Woodle

Tremblay

Brailey³

et al. 2020

American Journal of Transplantation

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“…At the cellular level, these effects were shown to involve two major pathways of disease development, namely cytokine secretion and T helper cell differentiation [15]. 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 [3,8,10,12,16,17]. Additionally, ONX 0914 treatment prevented the differentiation of naïve T helper cells to polarized Th17 cells in vitro [3,7,14,18].…”

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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“…Two major pathways involved in disease development are affected by LMP7 inhibition, namely, cytokine secretion and T helper cell differentiation. LMP7 inhibition of T cell receptor (TCR)‐activated T cells and endotoxin‐stimulated human peripheral blood mononuclear cells (PBMCs) or mouse splenocytes strongly reduced the secretion of numerous pro‐inflammatory cytokines (Muchamuel et al, ; Basler et al, ; ; ; ; Ichikawa et al, ; Sula Karreci et al, ). Additionally, LMP7 inhibition prevents the differentiation of naïve T helper cells to polarized Th17 cells in vitro (Muchamuel et al, ; Kalim et al, ; Liu et al, ).…”

Section: Introductionmentioning

confidence: 99%

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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Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

Cited by 59 publications

References 32 publications

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells

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

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

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