Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells

Verteuil, Danielle A. de; Rouette, Alexandre; Hardy, Marie-Pierre; Lavallée, Stéphanie; Trofimov, Assya; Gaucher, Étienne; Perreault, Claude

doi:10.4049/jimmunol.1400871

Cited by 30 publications

(39 citation statements)

References 56 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To evaluate the role(s) of IPs in mTEC biology, we compared the thymi of WT mice to those of mice with targeted inactivation of genes encoding two IP subunits (Psmb8 and Psmb10; hereafter referred to as double-knockout [dKO] mice). Because of the cooperative rules of IP catalytic subunit assembly, cells from these mice are almost totally IP deficient, because in addition to the total lack of PSMB8 and PSMB10, they contain low levels of PSMB9 ( Figure S3B) (de Verteuil et al, 2014). Consistent with a previous report (Kincaid et al, 2011), we found that the frequency of CD8 single-positive thymocytes was decreased in dKO mice relative to WT mice ( Figure 2B).…”

Section: Ips Selectively Regulate Mtec Cellularity In a Cell-autonomosupporting

confidence: 91%

“…Nuclear factor kB (NF-kB) and tumor necrosis factor signaling regulate mTEC differentiation, and mice deficient in receptor activator of nuclear factor-kB (RANK), CD40, or LTbR have a small thymic medulla and develop autoimmunity (Akiyama et al, 2008;Chin et al, 2003). Because IPs and CPs differentially regulate the activation of these signaling pathways (de Verteuil et al, 2014), we surmised that mTEC defects in dKO mice could result from dysregulated mTEC differentiation. We therefore isolated mTEC lo and mTEC hi from WT and dKO mice and analyzed the mRNA expression profiles of genes that control mTEC differ-entiation and thymic medulla formation.…”

Section: Mature Mtecs From Ip-deficient Mice Have a Reducedmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Ips Selectively Regulate Mtec Cellularity In a Cell-autonomosupporting

confidence: 91%

Section: Mature Mtecs From Ip-deficient Mice Have a Reducedmentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…RNA extraction and high-throughput RNA-seq RNA extraction and RNA-seq were performed as described (25,26). Output data were mapped to the Mus muculus (mm10) reference genome using ELANDv2 alignment tool from the CASAVA 1.8.2 software, and transcript levels were expressed as reads per kilobase of exon per million mapped reads (RPKM) (27).…”

Section: Flow Cytometry and Cell Sortingmentioning

confidence: 99%

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

Patenaude

Perreault

2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

In order to understand the role of mesenchymal cells (MCs) in the adult thymus, we performed whole transcriptome analyses of primary thymic, bone, and skin MCs. These three MC populations shared expression of 2850 core MC genes involved in generic processes including interactions with tissue-resident macrophages. Moreover, we discovered that 2036 genes were differentially expressed, by at least 5-fold, in the three MC populations. Genes preferentially expressed in thymic MCs are instrumental in clearance of apoptotic thymocytes by macrophages, maintenance of a noninflammatory milieu, and attraction-expansion of thymocyte progenitors. Thymic and bone MCs share other sets of differentially expressed genes implicated in resolution of inflammation and expansion of hematolymphoid progenitors. Consistent with the fact that thymic and skin MCs have to support epithelial cells, they express at higher levels genes mediating epithelial cell adhesion to basement membrane and mesenchymal–epithelial cross-talk. Differentially expressed genes preferentially expressed by bone MCs are connected to formation and remodeling of bone, whereas those preferentially expressed in skin MCs are involved in skin and hair follicle homeostasis. We conclude that MCs from different organs display substantial heterogeneity and that the transcriptome of thymic MCs is exquisitely suited for interactions with epithelial and hematolymphoid cells in an environment with a high apoptosis rate.

show abstract

“…Until now, it is unresolved how these changes in immune cell function are mediated. Immunoproteasome deficiency has been shown to influence the transcriptome of immune cells, which might be the result of altered substrate turnover in immunoproteasome-deficient cells (57,112,113). One explanation might be that immunoproteasomes increase the general pool of proteasomal catalytic capacity (50).…”

Section: Immunoproteasomes Shape Immune Cell Function and Innate Immumentioning

confidence: 99%

Proteasome function shapes innate and adaptive immune responses

Kammerl

Meiners

2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

The proteasome system degrades more than 80% of intracellular proteins into small peptides. Accordingly, the proteasome is involved in many essential cellular functions, such as protein quality control, transcription, immune responses, cell signaling, and apoptosis. Moreover, degradation products are loaded onto major histocompatibility class I molecules to communicate the intracellular protein composition to the immune system. The standard 20S proteasome core complex contains three distinct catalytic active sites that are exchanged upon stimulation with inflammatory cytokines to form the so-called immunoproteasome. Immunoproteasomes are constitutively expressed in immune cells and have different proteolytic activities compared with standard proteasomes. They are rapidly induced in parenchymal cells upon intracellular pathogen infection and are crucial for priming effective CD8(+) T-cell-mediated immune responses against infected cells. Beyond shaping these adaptive immune reactions, immunoproteasomes also regulate the function of immune cells by degradation of inflammatory and immune mediators. Accordingly, they emerge as novel regulators of innate immune responses. The recently unraveled impairment of immunoproteasome function by environmental challenges and by genetic variations of immunoproteasome genes might represent a currently underestimated risk factor for the development and progression of lung diseases. In particular, immunoproteasome dysfunction will dampen resolution of infections, thereby promoting exacerbations, may foster autoimmunity in chronic lung diseases, and possibly contributes to immune evasion of tumor cells. Novel pharmacological tools, such as site-specific inhibitors of the immunoproteasome, as well as activity-based probes, however, hold promises as innovative therapeutic drugs for respiratory diseases and biomarker profiling, respectively.

show abstract

Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells

Cited by 30 publications

References 56 publications

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

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

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

Proteasome function shapes innate and adaptive immune responses

Contact Info

Product

Resources

About