Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients

Bhatt, DK; Stan, Razvan C.; Pinhata, R; Machado, Maria Aparecida de Andrade Moreira; Maity, Shuvadeep; Cunningham‐Rundles, Charlotte; Vogel, Christine; Camargo, Maristela Martins de

doi:10.1111/cei.13410

Cited by 4 publications

(3 citation statements)

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“…The most downregulated pathways were interferon-a response, followed by pathways influencing cell metabolism (fatty acid metabolism, protein secretion, and oxidative phosphorylation). Recent studies have determined alterations in these pathways in CVID patients (43)(44)(45). In CSM B cells, we found the same dysregulated pathways and more (Supplementary Figure 2B).…”

Section: Transcriptome Landscape Of Unstimulated Naïve B Cells From T...supporting

confidence: 77%

Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI

Ramirez

Posadas-Cantera²,

Langer³

et al. 2022

Front. Immunol.

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Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary immunodeficiency in humans. The genetic cause of CVID is still unknown in about 70% of cases. Ten percent of CVID patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding TACI. Mutations in TNFRSF13B alone may not be sufficient for the development of CVID, as 1% of the healthy population carry these mutations. The common hypothesis is that TACI mutations are not fully penetrant and additional factors contribute to the development of CVID. To determine these additional factors, we investigated the perturbations of transcription factor (TF) binding and the transcriptome profiles in unstimulated and CD40L/IL21-stimulated naïve B cells from CVID patients harboring the C104R mutation in TNFRSF13B and compared them to their healthy relatives with the same mutation. In addition, the proteome of stimulated naïve B cells was investigated. For functional validation, intracellular protein concentrations were measured by flow cytometry. Our analysis revealed 8% less accessible chromatin in unstimulated naïve B cells and 25% less accessible chromatin in class-switched memory B cells from affected and unaffected TACI mutation carriers compared to healthy donors. The most enriched TF binding motifs in TACI mutation carriers involved members from the ETS, IRF, and NF-κB TF families. Validation experiments supported dysregulation of the NF-κB and MAPK pathways. In steady state, naïve B cells had increased cell death pathways and reduced cell metabolism pathways, while after stimulation, enhanced immune responses and decreased cell survival were detected. Using a multi-omics approach, our findings provide valuable insights into the impaired biology of naïve B cells from TACI mutation carriers.

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Section: Transcriptome Landscape Of Unstimulated Naïve B Cells From T...supporting

confidence: 77%

Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI

Ramirez

Posadas-Cantera²,

Langer³

et al. 2022

Front. Immunol.

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“…However, Atxn3 KO MEFs treated with DMSO did show a 35% decrease of total K48-Ub compared with MEFs derived from WT littermates (Figure 3B), an effect that was not observed in baseline conditions (data not shown). This latter observation suggests that Atxn3-mediated effects on K48-Ub changes are impacted by DMSO, which is known to alter cellular conditions in a concentration-dependent manner (Braden and Neufeld, 2016;Dludla et al, 2018;Bhatt et al, 2020). Moreover, proteasomal inhibition in Atxn3 KO and WT MEFs led to similar increases in the levels of all types of K63-Ub proteins (Figure 3C) confirming that K63-Ub species also signal for proteasomal degradation (Ohtake et al, 2018).…”

Section: Atxn3 Affects Levels Of Hmw K48-ub Proteins In Mouse Embryon...mentioning

confidence: 56%

Regional and age-dependent changes in ubiquitination in cellular and mouse models of spinocerebellar ataxia type 3

Luo

Todi

Paulson

et al. 2023

Front. Mol. Neurosci.

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Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in the ATXN3 gene that encodes an expanded tract of polyglutamine in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murine Atxn3 or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed in the cerebellum and brainstem of 7- and 47-week-old Atxn3 knockout and SCA3 transgenic mice, and also in relevant mouse and human cell lines. In older mice, we observed that wild-type ATXN3 impacts the cerebellar levels of K48-Ub proteins. In contrast, pathogenic ATXN3 leads to decreased brainstem abundance of K48-Ub species in younger mice and changes in both cerebellar and brainstem K63-Ub levels in an age-dependent manner: younger SCA3 mice have higher levels of K63-Ub while older mice have lower levels of K63-Ub compared to controls. Human SCA3 neuronal progenitor cells also show a relative increase in K63-Ub proteins upon autophagy inhibition. We conclude that wild-type and mutant ATXN3 differentially impact K48-Ub- and K63-Ub-modified proteins in the brain in a region- and age-dependent manner.

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“…Sir —The interesting paper by Bhatt et al on unfolded protein response (UPR) in B cells from common variable immunodeficiency (CVID) patients highlights the complex nature of this acquired immunodeficiency disorder . This paper allows understanding of endoplasmic reticulum (ER) stress response in the early hours, as longer exposures to tunicamycin or thapsigargin would have activated pro‐apoptotic pathways and eventual cell death .…”

mentioning

confidence: 99%

Do ribosomal protein alterations affect ER stress response in CVID?

Khan

2020

Clinical and Experimental Immunology

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Chemical chaperones reverse early suppression of regulatory circuits during unfolded protein response in B cells from common variable immunodeficiency patients

Cited by 4 publications

References 58 publications

Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI

Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI

Regional and age-dependent changes in ubiquitination in cellular and mouse models of spinocerebellar ataxia type 3

Do ribosomal protein alterations affect ER stress response in CVID?

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