The ubiquitin–proteasome system plays essential roles in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8+ T cells

Duan, Xuefeng; Hisaeda, Hajime; Shen, Jianying; Tu, Liping; Imai, Takashi; Chou, Bin; Murata, Shigeo; Chiba, Tomoki; Tanaka, Keiji; Fehling, Hans Jörg; Koga, Tomohiro; Sueishi, Katsuo; Himeno, Kunisuke

doi:10.1093/intimm/dxl005

Cited by 19 publications

(15 citation statements)

References 53 publications

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“…The efficiency of peptide cleavage by the immunoproteasome is higher than by the constitutive proteasome [5] . Mice lacking the LMP7 subunit have reduced antigen presentation [6] . Recently, interferon type 1 (IFNa) has been reported as an effective inducer of immunoproteasome in liver cells [7] .…”

Section: Proteasome Structure and Functionsmentioning

confidence: 99%

Implication of altered proteasome function in alcoholic liver injury

Osna¹

2007

WJG

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The proteasome is a major protein-degrading enzyme, which catalyzes degradation of oxidized and aged proteins, signal transduction factors and cleaves peptides for antigen presentation. Proteasome exists in the equilibrium of 26S and 20S particles. Proteasome function is altered by ethanol metabolism, depending on oxidative stress levels: low oxidative stress induces proteasome activity, while high oxidative stress reduces it. The proposed mechanisms for modulation of proteasome activity are related to oxidative modification of proteasomal proteins with primary and secondary products derived from ethanol oxidation. Decreased proteolysis by the proteasome results in the accumulation of insoluble protein aggregates, which cannot be degraded by proteasome and which further inhibit proteasome function. Mallory bodies, a common signature of alcoholic liver diseases, are formed by liver cells, when proteasome is unable to remove cytokeratins. Proteasome inhibition by ethanol also promotes the accumulation of pro-apoptotic factors in mitochondria of ethanol-metabolizing liver cells that are normally degraded by proteasome. In addition, decreased proteasome function also induces accumulation of the negative regulators of cytokine signaling (I-kappaB and SOCS), thereby blocking cytokine signal transduction. Finally, ethanol-elicited blockade of interferon type 1 and 2 signaling and decreased proteasome function impairs generation of peptides for MHC class I-restricted antigen presentation.

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Section: Proteasome Structure and Functionsmentioning

confidence: 99%

Implication of altered proteasome function in alcoholic liver injury

Osna¹

2007

WJG

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“…Mice deficient in LMP7, a molecule responsible for major chymotrypsin activity, exhibited attenuated antigen presenting activity [24]. We previously showed that LMP7 plays a crucial role in inducing antigen-specific CD8 + T cells, and LMP7-deficient mice were more susceptible to tumors [25] and protozoan infection [26], [27], where CD8 T cells mainly function as effector cells.…”

Section: Introductionmentioning

confidence: 99%

Resistance to Malaria by Enhanced Phagocytosis of Erythrocytes in LMP7-deficient Mice

et al. 2013

Self Cite

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General cellular functions of proteasomes occur through protein degradation, whereas the specific function of immunoproteasomes is the optimization of antigen processing associated with MHC class I. We and others previously reported that deficiency in subunits of immunoproteasomes impaired the activation of antigen-specific CD8+ T cells, resulting in higher susceptibility to tumor and infections. We demonstrated that CD8+ T cells contributed to protection against malaria parasites. In this study, we evaluated the role of immunoproteasomes in the course of infection with rodent malaria parasites. Unexpectedly, Plasmodium yoelii infection of mice deficient in LMP7, a catalytic subunit of immunoproteasomes, showed lower parasite growth in the early phase of infection and lower lethality compared with control mice. The protective characteristics of LMP7-deficient mice were not associated with enhanced immune responses, as the mutant mice showed comparable or diminished activation of innate and acquired immunity. The remarkable difference was observed in erythrocytes instead of immune responses. Parasitized red blood cells (pRBCs) purified from LMP7-deficient mice were more susceptible to phagocytosis by macrophages compared with those from wild-type mice. The susceptibility of pRBC to phagocytosis appeared to correlate with deformity of the membrane structures that were only observed after infection. Our results suggest that RBCs of LMP7-deficient mice were more likely to deform in response to infection with malaria parasites, presumably resulting in higher susceptibility to phagocytosis and in the partial resistance to malaria.

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“…However, the effect of decreased protein stability may not have this effect for vectors that target different cells of the host immune system. Several studies of antigens targeted for more rapid proteasomal degradation have found that delivery of rapidly degraded antigens stimulates an enhanced cellular immune response in vivo when delivered by DNA vaccination (Andersson and Barry, 2004;Delogu et al, 2000;Duan et al, 2006;Rodriguez et al, 1998;Rodriguez, Zhang, and Whitton, 1997;Wu and Kipps, 1997) or by recombinant vaccinia virus (Tobery and Siliciano, 1997;Townsend et al, 1988). As suggested previously by several groups (Andersson and Barry, 2004;Huckriede et al, 2004;Whitton et al, 1999), more efficient processing and presentation of an antigen would be predicted to increase its ability to induce a cellular immune response if the vector targets a professional APC, and if production of appropriately processed peptides from the unaltered antigen is the limiting step in immune induction.…”

Section: Introductionmentioning

confidence: 99%

Effects of rapid antigen degradation and VEE glycoprotein specificity on immune responses induced by a VEE replicon vaccine

Fluet¹,

Whitmore

Moshkoff

et al. 2008

Virology

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Genetic vaccines are engineered to produce immunogens de novo in the cells of the host for stimulation of a protective immune response. In some of these systems, antigens engineered for rapid degradation have produced an enhanced cellular immune response by more efficient entry into pathways for processing and presentation of MHC class I peptides. VEE replicon particles (VRP), single cycle vaccine vectors derived from Venezuelan equine encephalitis virus (VEE), are examined here for the effect of an increased rate of immunogen degradation on VRP vaccine efficacy. VRP expressing the matrix capsid (MA/CA) portion of SIV Gag were altered to promote rapid degradation of MA/CA by various linkages to co-translated ubiquitin or by destabilizing mutations and were used to immunize BALB/c mice for quantitation of anti-MA/CA cellular and humoral immune responses. Rapid degradation by the N-end rule correlated with a dampened immune response relative to unmodified MA/CA when the VRP carried a glycoprotein spike from an attenuated strain of VEE. In contrast, statistically equivalent numbers of IFNgamma(+)T-cells resulted when VRP expressing unstable MA/CA were packaged with the wild-type VEE glycoproteins. These results suggest that the cell types targeted in vivo by VRP carrying mutant or wild type glycoprotein spikes are functionally different, and are consistent with previous findings suggesting that wild-type VEE glycoproteins preferentially target professional antigen presenting cells that use peptides generated from the degraded antigen for direct presentation on MHC.

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The ubiquitin–proteasome system plays essential roles in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8+ T cells

Cited by 19 publications

References 53 publications

Implication of altered proteasome function in alcoholic liver injury

Implication of altered proteasome function in alcoholic liver injury

Resistance to Malaria by Enhanced Phagocytosis of Erythrocytes in LMP7-deficient Mice

Effects of rapid antigen degradation and VEE glycoprotein specificity on immune responses induced by a VEE replicon vaccine

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