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

Abstract

The sole nonredundant role of the thymic medulla is to induce central tolerance, a vital process that depends on promiscuous gene expression (pGE), a unique feature of medullary thymic epithelial cells (mTECs). Although pGE enhances transcription of >3,000 genes in mTECs, its impact on the regulation of protein homeostasis remains unexplored. Here, we report that, because of pGE, mature mTECs synthesize substantially more proteins than other cell types and are exquisitely sensitive to loss of immunoproteasomes (IPs). Indeed, IP deficiency causes proteotoxic stress in mTECs and leads to exhaustion of postnatal mTEC progenitors. Moreover, IP-deficient mice show accelerated thymic involution, which is characterized by a selective loss of mTECs and multiorgan autoimmune manifestations. We conclude that pGE, the quintessential feature of mTECs, is a major burden for the maintenance of proteostasis, which is alleviated by the constitutive expression of IPs in mTECs.

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

“…In this context acini and macrophages were affected, considering that IL-1β is exclusively expressed by macrophages (14). Besides the differences detected in cytokine production, we also observed that immunoproteasome deficiency (55)(56). In our work, we show that the immunoproteasome is crucial for limiting UPR activation in isolated pancreatic acini.…”

“…The UPR restores ER protein homeostasis through inhibition of protein synthesis, enhancement of protein folding and degradation mechanisms, such as autophagy and the UPS (20). Recently, the UPR and the immunoproteasome have appeared as pivotal networks in the maintenance of protein homeostasis and cell fate control (55–56). In our work, we show that the immunoproteasome is crucial for limiting UPR activation in isolated pancreatic acini.…”

“…As a consequence of UPR dysregulation, represented by a prolonged time span for activation of sensor proteins and downstream targets, cell death appears to be the outcome (56). As verified by pancreas histology, immunoproteasome dysfunction correlated with sustained pancreatic damage, which was accompanied by increased acinar cell death, namely apoptosis and necrosis.…”

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

“…The expression of HSP70 chaperones increases in response to various stressful stimuli, especially those causing oxidative stress or endoplasmic reticulum stress (40). We did not find signs of endoplasmic reticulum stress in the DEG dataset according to biomarker gene expression (41). However, thymocytes from Psmb11 2 /2 mice showed upregulation of several oxidantinduced transcripts, namely Fos, Jun, Hsph1, Hspa1a, Hspa1b, Gadd45, and Hmox1 (heme oxygenase) (42) (Fig.…”

Biological consequences of structural and functional proteasome diversity

“…Moreover, iPs facilitate degradation of oxidized proteins and maintain cellular homeostasis during stress ( Pickering et al., 2010 ; Yun et al., 2016 ). Recent study by St-Pierre and coauthors highlight the role of Ips in adaptation of medullary thymic epithelial cells characterized by high levels of protein synthesis to proteotoxic stress ( St-Pierre et al., 2017 ). In addition, iPs were proposed to be involved in production of peptides which participate in cell-cell interactions in order to maintain nervous system plasticity in mice lacking β2-microglobulin ( Lyupina et al., 2013 ).…”