Immunoproteasome subunit ß5i/LMP7-deficiency in atherosclerosis

Abstract

Management of protein homeostasis by the ubiquitin-proteasome system is critical for atherosclerosis development. Recent studies showed controversial results on the role of immunoproteasome (IP) subunit β5i/LMP7 in maintenance of protein homeostasis under cytokine induced oxidative stress. The present study aimed to investigate the effect of β5i/LMP7-deficiency on the initiation and progression of atherosclerosis as a chronic inflammatory, immune cell driven disease. LDLR−/−LMP7−/− and LDLR−/− mice were fed a Western-type diet for either 6 or 24 weeks to induce early and advanced stage atherosclerosis, respectively. Lesion burden was similar between genotypes in both stages. Macrophage content and abundance of polyubiquitin conjugates in aortic root plaques were unaltered by β5i/LMP7-deficiency. In vitro experiments using bone marrow-derived macrophages (BMDM) showed that β5i/LMP7-deficiency did not influence macrophage polarization or accumulation of polyubiquitinated proteins and cell survival upon hydrogen peroxide and interferon-γ treatment. Analyses of proteasome core particle composition by Western blot revealed incorporation of standard proteasome subunits in β5i/LMP7-deficient BMDM and spleen. Chymotrypsin-, trypsin- and caspase-like activities assessed by using short fluorogenic peptides in BMDM whole cell lysates were similar in both genotypes. Taken together, deficiency of IP subunit β5i/LMP7 does not disturb protein homeostasis and does not aggravate atherogenesis in LDLR−/− mice.

Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice

“…Here, the results presented showed that β5i was upregulated in the atherosclerotic plaques of eKO mice (Figure ); genetic ablation or inhibition of β5i reduced lesional accumulation of apoptotic cells but enhanced MERTK‐mediated efferocytosis, therefore inhibited necrotic core formation and atherosclerosis progression (Figures ). However, our results are inconsistent with a recent study that showed that β5i deficiency had no significant effect on the initiation and progression of atherosclerosis in the LDL receptor KO mice fed with ATD . This is not the first time that gene function studies carried out in these two mouse models have yielded totally different results.…”

Immunoproteasomes Control the Homeostasis of Medullary Thymic Epithelial Cells by Alleviating Proteotoxic Stress

“…It is noteworthy that deletion of both PSMB8 and PSMB10 subunits was required to decrease mTEC cellularity ( Figure 2F). Hence, consistent with a recent report (Hewing et al, 2017), the single deletion of PSMB8 (LMP7) appears insufficient to cause proteotoxic stress. Additionally, using in vivo approaches (i.e., thymus transplantation and systemic poly(I:C) administration), we showed that IP deficiency has a dramatic impact on the regenerative potential of mTECs.…”

Immunoproteasome deficiency leads to sustained pancreatic injury and delayed recovery from experimental pancreatitis

“…Notably, the β5i/LMP7 subunit but not the β5 constitutive subunit was up-regulated in an in vitro and an in vivo model of pancreatitis. Increased β5 protein levels in acini from β5i/LMP7-deficient mice were observed as a compensatory mechanism, as seen before in other cell types (46–47). However, from the data obtained in this study, the immunoproteasome represents the major proteasome type involved in a rapid and efficient response to inflammation and ER stress during pancreatitis.…”

“…The UPR encircles stress response signaling pathways triggered by accumulation of misfolded or damaged proteins in the ER lumen (57). Although some studies did not report differences in the capacities of the constitutiveand the immunoproteasome to degrade ubiquitinated protein targets (47,58), our work supports an essential role of the immunoproteasome in regulating this process and synchronizing UPR activation in pancreatitis. Unbalanced UPR, due to proteasome dysfunction has been implicated in the innate immune response, with the immunoproteasome playing a central role in the regulation of inflammation and UPR.…”