Regulation and function of poised mRNAs in lymphocytes

Turner, Martin

doi:10.1002/bies.202200236

Cited by 8 publications

(2 citation statements)

References 179 publications

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“…Expression of cytokine mRNAs without an apparent inflammatory response suggests that the mRNAs are not translated to cytokines under homeostatic conditions. The presence of preformed cytokine mRNA in T cells under homeostatic conditions was noted in previous studies ( 38–43 ), however, the mechanism of translational repression and its relevance for tissue-specific immunity in health and disease remained elusive. Our results reveal that pathways associated with global mRNA translation, ribosomal biogenesis, and mRNA translation initiation are significantly suppressed in CD4 + Trm cells in homeostasis, suggesting that attenuation of mRNA translation is major mechanism to restrict Trm cell activity and thereby prevent tissue inflammation.…”

Section: Discussionmentioning

confidence: 68%

The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4⁺T cells

Asada,

Ginsberg,

Paust

et al. 2024

Preprint

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Tissue-resident memory T (Trm) cells are a specialized T cell population that resides in tissues and can play both a protective and pathogenic role. The mechanism that enables Trm cells to provide a rapid protective response while restricting their function in homeostasis remains unclear. Here, we show that human and mouse CD4+Trm cells exist in a poised state, characterized by storage of proinflammatory type-1 and type-3 cytokine mRNAs without protein production. In steady-state conditions, cytokine mRNA translation in Trm cells is suppressed by the integrated stress response (ISR)/eIF2α pathway, whereas Trm-cell activation under inflammatory conditions results in eIF2α dephosphorylation, leading to derepression and rapid translation of the cytokine mRNAs stored in stress granules. Pharmacological inhibition of eIF2α dephosphorylation resulted in reduced cytokine production from Trm cells, and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in Trm cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine. Our results identify ISR/eIF2α-mediated control of cytokine mRNA translation as an underlying mechanism that restricts Trm cell activity in homeostasis but also promotes rapid response upon local infection or autoimmune reaction.

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Section: Discussionmentioning

confidence: 68%

The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4⁺T cells

Asada,

Ginsberg,

Paust

et al. 2024

Preprint

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“…Otherwise, to our knowledge, such prolonged ribosomal stalling has not been described in mammalian cells. These experiments may also be useful in examining the phenomenon of “poised mRNA”, originally described in lymphocytes for cytokine mRNAs and more recently expanded on with advanced sequencing techniques 48,49 .…”

Section: Discussionmentioning

confidence: 99%

Paradox Found: Global Accounting of Lymphocyte Protein Synthesis

Seedhom¹,

Dersh²,

Hollý³

et al. 2022

Preprint

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Rapid lymphocyte cell division places enormous demands on the protein synthesis machinery. Flow cytometric measurement of puromycylated ribosome-associated nascent chains after treating cells or mice with translation initiation inhibitors reveals that ribosomes in resting lymphocytes in vitro and in vivo elongate at typical rates for mammalian cells. Intriguingly, elongation rates can be increased up to 30% by activation in vivo or fever temperature in vitro. Resting and activated lymphocytes possess abundant monosome populations, most of which actively translate in vivo, while in vitro, nearly all can be stalled prior to activation. Quantitating lymphocyte protein mass and translating ribosomes reveals a paradoxically high ratio of cellular protein to ribosomes insufficient to support their rapid in vivo division, suggesting that the activated lymphocyte proteome in vivo may be generated in an unusual manner. Our findings demonstrate the importance of a global understanding of protein synthesis in lymphocytes and other rapidly dividing immune cells.

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Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity

Schmidt,

Raj,

O'Neill

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Constitutive activation of the MALT1 paracaspase in conventional T cells of Malt1 TBM/TBM (TRAF6 Binding Mutant = TBM) mice causes fatal inflammation and autoimmunity, but the involved targets and underlying molecular mechanisms are unknown. We genetically rendered a single MALT1 substrate, the RNA-binding protein (RBP) Roquin-1, insensitive to MALT1 cleavage. These Rc3h1 Mins/Mins mice showed normal immune homeostasis. Combining Rc3h1 Mins/Mins alleles with those encoding for constitutively active MALT1 (TBM) prevented spontaneous T cell activation and restored viability of Malt1 TBM/TBM mice. Mechanistically, we show how antigen/MHC recognition is translated by MALT1 into Roquin cleavage and derepression of Roquin targets. Increasing T cell receptor (TCR) signals inactivated Roquin more effectively, and only high TCR strength enabled derepression of high-affinity targets to promote Th17 differentiation. Induction of experimental autoimmune encephalomyelitis (EAE) revealed increased cleavage of Roquin-1 in disease-associated Th17 compared to Th1 cells in the CNS. T cells from Rc3h1 Mins/Mins mice did not efficiently induce the high-affinity Roquin-1 target IκB NS in response to TCR stimulation, showed reduced Th17 differentiation, and Rc3h1 Mins/Mins mice were protected from EAE. These data demonstrate how TCR signaling and MALT1 activation utilize graded cleavage of Roquin to differentially regulate target mRNAs that control T cell activation and differentiation as well as the development of autoimmunity.

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Regulation and function of poised mRNAs in lymphocytes

Cited by 8 publications

References 179 publications

The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4⁺T cells

The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4⁺T cells

Paradox Found: Global Accounting of Lymphocyte Protein Synthesis

Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity

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Regulation and function of poised mRNAs in lymphocytes

Cited by 8 publications

References 179 publications

The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4+T cells

The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4+T cells

Paradox Found: Global Accounting of Lymphocyte Protein Synthesis

Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity

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The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4⁺T cells

The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4⁺T cells