Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

Fissolo, Nicolás; Kraus, Marianne; Reich, Michael; Ayturan, Miriam; Overkleeft, Herman S.; Driessen, Christoph; Weissert, Robert

doi:10.1002/eji.200838413

Cited by 65 publications

(55 citation statements)

References 36 publications

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“…Pharmacological inhibition with bortezomib ameliorated glomerulonephritis and prolonged the survival of two mouse strains with lupus-like disease (48), attenuated murine collagen-induced arthritis (49), reduced colitis development in a rat model (30), and ameliorated autoimmune encephalomyelitis in mice and rats in prophylactic and therapeutic treatment (50). It is well established that bortezomib inhibits NF-kB activation by blocking the degradation of the NF-kB inhibitor (I-kB), leading to reduced expression of proinflammatory factors, such as cytokines and chemokines, and adhesion molecules on lymphoid cells.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

Basler

Dajee²,

Moll

et al. 2010

The Journal of Immunology

215

236

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Section: Discussionmentioning

confidence: 99%

Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

Basler

Dajee²,

Moll

et al. 2010

The Journal of Immunology

215

236

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“…Bortezomib was recently shown to have additive effects with a cathepsin S inhibitor in a mouse model of multiple sclerosis (29). Thus, peptide vinyl sulfones that target proteasome chymotrypsin-like activity and cathepsins may find therapeutic applications in the treatment of autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

Nature of Pharmacophore Influences Active Site Specificity of Proteasome Inhibitors

Screen

Britton

Downey-Kopyscinski

et al. 2010

Journal of Biological Chemistry

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Proteasomes degrade most proteins in mammalian cells and are established targets of anti-cancer drugs. The majority of proteasome inhibitors are composed of short peptides with an electrophilic functionality (pharmacophore) at the C terminus. All eukaryotic proteasomes have three types of active sites as follows: chymotrypsin-like, trypsin-like, and caspase-like. It is widely believed that active site specificity of inhibitors is determined primarily by the peptide sequence and not the pharmacophore. Here, we report that active site specificity of inhibitors can also be tuned by the chemical nature of the pharmacophore. Specifically, replacement of the epoxyketone by vinyl sulfone moieties further improves the selectivity of ␤5-specific inhibitors NC-005, YU-101, and PR-171 (carfilzomib). This increase in specificity is likely the basis of the decreased cytotoxicity of vinyl sulfone-based inhibitors to HeLa cells as compared with that of epoxyketone-based inhibitors.The ubiquitin-proteasome pathway is essential in the maintenance of protein homeostasis in all eukaryotic cells and is involved in the regulation of numerous biologic processes. Proteasome inhibition causes apoptosis of malignant cells (1, 2). The proteasome inhibitor bortezomib (Velcade, PS-341) is used for the treatment of multiple myeloma and mantle cell lymphoma. Four other proteasome inhibitors are at different stages of clinical trials (3-6).The 26 S proteasome is a large (1.6 -2.4 MDa), hollow cylindrical, and multifunctional particle that consists of a 20 S proteolytic core and one or two 19 S regulatory complexes. Each eukaryotic 20 S core particle has three pairs of proteolytic sites with distinct substrate specificities (7-11). The ␤5 proteolytic sites are "chymotrypsin-like," and the ␤2 sites are "trypsin-like." The ␤1 sites cleave after acidic residues (Glu and Asp) and are referred to as "post-acidic," "post-glutamate peptide hydrolase," or "caspase-like." Tissues of the immune system also express immunoproteasomes, in which ␤5, ␤1, and ␤2 catalytic subunits are replaced by their major histocompatibility complex (MHC) locus-encoded counterparts LMP7 (␤5i), LMP2 (␤1i), and MECL-1 (␤2i).The chymotrypsin-like sites have long been considered the only suitable targets for anti-neoplastic agents and are the primary targets of all these agents. However, our recent work indicates that cytotoxicity of proteasome inhibitors correlates poorly with exclusive inhibition of the chymotrypsin-like sites and that co-inhibition of other sites is usually needed to achieve maximal cytotoxicity (12). In this regard, we have considered it of interest to determine whether inhibitors with increased specificity for ␤5 display decreased cytotoxicity.Many structural classes of proteasome inhibitors are known (2, 13). The majority of these are N-terminally capped short peptides (2-4 residues) with an electrophilic trap at the C terminus (e.g. aldehydes, boronates, epoxyketones, and vinyl sulfones). This electrophile reacts with the catalytic N-terminal threonines ...

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“…This suggests that the ubiquitination rate either is very low or has been adjusted to avoid the otherwise deleterious accumulation of ubiquitinated protein aggregates that would drive cellular stress responses, eventually leading to apoptotic cell death (38). It is interesting to note that the literature also reports that proteasome inhibition may be one way that cells ameliorate an inflammatory situation and minimize autoimmunity (39,40). In light of these findings, it is possible that the suppression of proteasome activity is an adaptive response on the part of the epididymis, designed to maintain a local tolerogenic environment toward spermatozoa in the face of a precipitous loss of IDO activity in the Ido1 Ϫ/Ϫ animals.…”

Section: Iaamentioning

confidence: 99%

Deficient Tryptophan Catabolism along the Kynurenine Pathway Reveals That the Epididymis Is in a Unique Tolerogenic State

Jrad-Lamine

Henry-Berger

Gourbeyre

et al. 2011

Journal of Biological Chemistry

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Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1 ؊/؊ -deficient mice. In the caput epididymis of Ido1؊/؊ animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.Indoleamine 2,3-dioxygenase (IDO) 3 (EC 1.13.11.42) is the first and rate-limiting enzyme in Trp catabolism through the kynurenine pathway (Fig. 1). IDO is a ubiquitously expressed cytoplasmic protein typically activated by interferons (IFNs) (1-5). There is ample evidence that IDO mediates potent immunosuppression in classical immune responses as well as in fetal tolerance, tumor immune resistance, and regulation of autoimmune responses (1-3, 6 -8).Thirty years ago, Yoshida et al. (9) reported that rodent epididymal protein extracts exhibited a high IDO activity. Later, Takikawa et al. (10) demonstrated that unlike the classical cytokine-mediated expression of IDO encountered in nearly all mammalian tissues, the epididymal expression of IDO was constitutive and independent of IFN-␥. More recently, we have shown that IDO is expressed in a regionalized manner by both the principal and the apical cells of the most proximal epididymal region, the caput epididymis. To gain insights into the functions of IDO and the intermediates of the kynurenine pathway in the physiology of the mammalian epididymis, we measured the expression of IDO and related enzymes as well as the abundance of kynurenines and other Trp metabolites in both wild type (WT) and Ido1 Ϫ/Ϫ male mice. These data were correlated with light and electron microscopic analyses of epididymal epithelium, sperm count, sperm morphology, and fertility.

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Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

Cited by 65 publications

References 36 publications

Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

Nature of Pharmacophore Influences Active Site Specificity of Proteasome Inhibitors

Deficient Tryptophan Catabolism along the Kynurenine Pathway Reveals That the Epididymis Is in a Unique Tolerogenic State

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