Background: Viral infection and neoplastic transformation trigger endoplasmic reticulum (ER) stress. Thus, a large proportion of the cells that must be recognized by the immune system are stressed cells. Cells respond to ER stress by launching the unfolded protein response (UPR). The UPR regulates the two key processes that control major histocompatibility complex class I (MHC I)-peptide presentation: protein synthesis and degradation. We therefore asked whether and how the UPR impinges on MHC I-peptide presentation.
We identified a cluster of French-Canadian families with a new recessive ataxia of relatively pure cerebellar type caused by mutations in SYNE1. The function of SYNE1 is thus critical in the maintenance of cerebellar structure in humans. We expect that this disease will be a common cause of middle-age-onset recessive ataxia worldwide.
Background: By regulating protein degradation, constitutive proteasomes (CPs) regulate practically all fundamental cellular processes. Vertebrates also express immunoproteasomes (IPs), but the only well-established non-redundant role for IPs is their enhanced ability to generate peptides for MHC-I presentation. Results: Here we show that IPs regulate the expression of 8,104 genes in maturing bone marrow-derived dendritic cells (DCs). IPs regulated transcription of many mRNAs and maturation of a subset of them. These genes were separated into 15 different kinetic patterns, and Gene-Ontology analysis revealed enrichment linked to immune functions and housekeeping cellular processes, highlighting the complexity of the transcriptional cascade regulated by IPs. Notably, IPs’ impact on transcription was mediated through the non-redundant regulation of critical immune-related pathways, such as Nf-kB, STATs and IRFs. Furthermore, even when loaded with optimal amounts of SIINFEKL, IP-deficient DCs were inefficient for in vivo priming of OT-1 T cells. Conclusion: Our study shows that the role of IPs is not limited to antigen processing and highlights a new and critical role for IPs in regulation of gene expression. The dramatic impact of IPs on the transcriptional landscape could explain the various immune and non-immune phenotypes observed in vertebrates with IP-deficiency or -mutation.
IntroductionA Cardiology Evaluation Unit was established in 2004 within Québec’s Institut national d’excellence en santé et en services sociaux (INESSS) with a novel mandate to collect real-world evidence (RWE) to complement literature-based health technology assessment. In 2010 following publication of the seminal PARTNER trial, INESSS was mandated by the health ministry to review the evidence on transcatheter aortic valve intervention (TAVI) for patients with aortic stenosis. Herein we show how RWE was used to evaluate health system performance throughout the technology’s life cycle and inform organizational and clinical decisions.MethodsVarious products were diffused by INESSS over the years: a guidance (2012), an updated literature review (2017) and provincial standards (2017), in parallel with RWE reports covering TAVI use from 2013-2015, from 2013-2018, and a 2021 RWE report combined with administrative data covering transcatheter and surgical treatment of aortic stenosis from 2013-2019.ResultsBased on the guidance’s review of evidence, TAVI was initially recommended for patients considered at too high risk for the surgical approach, under the condition of continued evidence generation to address uncertainty. The subsequent literature review update highlighted that the indication for TAVI had been extended to patients at moderate surgical risk. INESSS produced standards in collaboration with clinical experts to optimize and harmonize the use of TAVI in designated centers. Evaluation of structures, processes and outcomes by INESSS continued until 2019, showing a continuous increase in the use of TAVI, improved short-term survival, and careful patient selection via a multidisciplinary process. RWE also highlighted the impact of TAVI on the overall organization of care for patients with aortic stenosis, as selection criteria further expanded to patients at lower surgical risk, raising important issues regarding patient selection processes, wait times, and longer-term outcomes.ConclusionsTAVI clinical practice is constantly evolving and leads to changes in the management of aortic stenosis. RWE provided essential organizational and clinical input to inform clinical guidance and decision-making by Québec policy-makers, clinicians and patients.
Background: Proteasomes play crucial roles in regulating fundamental cellular processes in eukaryotic cells. Catalytic subunits β1, β2 and β5 of the proteasome are replaced by LMP2, MECL-1 and LMP7 to form the immunoproteasome (IPr). We have shown that the IPr modulates mRNA levels of several clusters of genes in dendritic cells, but the precise mechanism by which it regulates gene expression is unknown. Results: By comparing transcriptome of Lmp7+/+/Mecl1+/+ (WT) and Lmp7-/-/Mecl1-/- (dKO) thymocytes by microarray, we found that the IPr affects the expression of 50 transcripts. The genes source of these transcripts are clustered in the genome, and are enriched in cell cycle-associated functions. Moreover, an overlap of 2% is seen by comparing with transcripts modulated by the IPr in dendritic cells. Chymotrypsin-like activity is higher in dKO than in WT cells, due to β5 overexpression. Furthermore, ubiquitinated proteins levels are similar between WT and dKO cells whereas free ubiquitin is lower in dKO cells. We next investigated levels of ubiquitin on histones, since it represent an important reservoir of ubiquitin and it can regulate transcriptional activity. Our results show that H2B, but not H2A, ubiquitination is increased in dKO cells. Conclusion: The effect of IPr on transcription is tissue-specific and could be due to increased ubiquitinated H2B levels. While proteasomes clearly regulate transcription, the impact of IPr on transcription has never been investigated.
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