An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells

Salerno, Fiamma; Howden, Andrew J. M.; Matheson, Louise S.; Gizlenci, Ozge; Screen, Michael; Lingel, Holger; Brunner‐Weinzierl, Monika C.; Turner, Martin

doi:10.1101/2022.12.22.521580

Cited by 3 publications

(7 citation statements)

References 98 publications

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“…Fig 6. Median LRRK2 copy numbers were quantified by label-free mass-spectrometry from WT splenocytes sorted into indicated subsets ((Salerno et al, 2023). Data accessed from Immunological Proteome Resource, immpres.co.uk.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

Dikovskaya,

Pemberton,

Taylor

et al. 2024

Preprint

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Mutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinson's Disease (PD) and Crohn's Disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we developed a flow cytometry-based assay to assess LRRK2 activity in individual cells and created EGFP-LRRK2-knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we catalogued LRRK2 level and activity in splenic and intestinal tissues. Inflammation increased LRRK2 expression and activity in B-cells, immature neutrophils and immature monocytes, but decreased these in dendritic cells and eosinophils. In mature neutrophils, inflammation stimulated LRRK2 activity but reduced EGFP-LRRK2 level. A kinase-activating PD-associated R1441C-LRRK2 mutation exacerbated inflammation-induced activation of LRRK2 specifically in monocytes and macrophages without affecting LRRK2 levels. Finally, we identified IL-4 as a novel factor that upregulated LRRK2 expression and activity in B-cells in vitro, replicating the inflammatory effects observed in vivo. Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD.

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Section: Resultsmentioning

confidence: 99%

Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

Dikovskaya,

Pemberton,

Taylor

et al. 2024

Preprint

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“…Examples of the processes in which poised mRNAs have been implicated. These include transcription factors; 6,14–16 signal transducers; 6,15,17 cytokines; 18–20,3–9 metabolic enzymes; 21 translation factors 17 and ribosomal subunits 17 …”

Section: The Cellular Contexts Of Untranslated Mrnamentioning

confidence: 99%

“…BCL6 antagonises the B cell to plasma cell fate decision, thus in activated B cells destined to become plasma cells Bcl6 mRNA presumably remains untranslated and its degradation may be actively promoted. Poised transcripts that encode mediators of B cell activation and differentiation are also found in immature and mature splenic B cells 15 …”

Section: The Cellular Contexts Of Untranslated Mrnamentioning

confidence: 99%

“…In anergic cells, the selective translational suppression of the IFNγ open reading frame (ORF) in the bicistronic IFNγ-YFP reporter F I G U R E 1 Examples of the processes in which poised mRNAs have been implicated. These include transcription factors; 6,14-16 signal transducers; 6,15,17 cytokines; [18][19][20][3][4][5][6][7][8][9] metabolic enzymes; 21 translation factors 17 and ribosomal subunits.…”

Section: T Cell Exhaustion and Anergymentioning

confidence: 99%

“…Poised transcripts that encode mediators of B cell activation and differentiation are also found in immature and mature splenic B cells. 15 When mitogen activated primary mouse B cells were treated with etoposide to induce an DNA damage 595 genes underwent changes in ribosome association but not mRNA abundance. 16 Amongst these were mRNAs encoding the TP53 and HIF1α transcription factors that were found to be associated with TIA1 in the absence of DNA damage.…”

Section: B Lymphocytesmentioning

confidence: 99%

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Regulation and function of poised mRNAs in lymphocytes

Turner

2023

BioEssays

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Pre-existing but untranslated or 'poised' mRNA exists as a means to rapidly induce the production of specific proteins in response to stimuli and as a safeguard to limit the actions of these proteins. The translation of poised mRNA enables immune cells to express quickly genes that enhance immune responses. The molecular mechanisms that repress the translation of poised mRNA and, upon stimulation, enable translation have yet to be elucidated. They likely reflect intrinsic properties of the mRNAs and their interactions with trans-acting factors that direct poised mRNAs away from or into the ribosome. Here, I discuss mechanisms by which this might be regulated.

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Longitudinal proteomic profiling of T cell differentiationin vivounveils dynamic proteome remodeling

Beusch,

Dawood,

Ozdilek

et al. 2024

Preprint

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T cell differentiation has been extensively studied on the cellular, transcriptional, and epigenetic levels. However, proteomic profiling of T cell differentiation directly ex-vivo has not been performed, despite numerous studies demonstrating discrepancy between transcriptional and proteomic profiles of cells. Here, we present the first exhaustive longitudinal proteomic profiling of T cell differentiation in vivo using the well-characterized lymphocytic choriomeningitis virus (LCMV) mouse model. We performed ex-vivo protein abundance profiling of effector to memory differentiation (Teff/Tmem) and early to late exhausted T cell (Tex) differentiation following LCMV infection with the acute Armstrong and chronic Clone-13 strains, respectively. Our results show dynamic alterations of the T cell proteome during differentiation that are either common or distinct for acute and chronic infection. Importantly, several proteins that are significantly abundant for a specific cell state were not previously highlighted by transcriptional profiling. Thus, our study provides a comprehensive resource for the proteome of in vivo T cell differentiation that could unravel novel protein interactions with potential therapeutic implications.

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An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells

Cited by 3 publications

References 98 publications

Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

Regulation and function of poised mRNAs in lymphocytes

Longitudinal proteomic profiling of T cell differentiationin vivounveils dynamic proteome remodeling

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