Abstract
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.
Highlights
The proteasome, a multicatalytic protease complex, is an essential component of the ATP-dependent proteolytic pathway that catalyzes the elimination of ubiquitinated proteins [1]
Infection with P. yoelii 17XNL (PyNL) caused a transient infection with a peak parasitemia up to 30% followed by complete eradication in WT mice (Fig. 1B)
LMP7-deficient mice infected with PyNL showed a significantly lower level of parasitemia during the course of infection and took a shorter time to recover from the infection (Fig. 1B)
Summary
The proteasome, a multicatalytic protease complex, is an essential component of the ATP-dependent proteolytic pathway that catalyzes the elimination of ubiquitinated proteins [1]. It is distributed in the nucleus and cytosol, where it can comprise 0.5 to 1.0% of total cellular protein [2]. The 26S proteasome catalyzes the rapid degradation of proteins that are covalently linked to polyubiquitin chains This pathway is highly regulated and selective, and in turn it regulates many important cellular processes such as transcriptional activation [3], cell-cycle progression [4], cell proliferation [5,6,7], differentiation [8,9] and apoptosis [10,11]. From the immunological point of view, proteasomal degradation of proteins is indispensable for antigen presentation associated with MHC class I, which activates CD8+ T cells [12]
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