The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity

Yi, Whikun; Gupta, Sanjay; Ricker, Edd; Manni, Michela; Jessberger, Rolf; Chinenov, Yurii; Molina, Henrik; Pernis, Alessandra B.

doi:10.1038/s41467-017-00348-3

Cited by 50 publications

(60 citation statements)

References 58 publications

(99 reference statements)

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“…Among 564 immune-related transcripts that were screened in this study, only 11 were identified as targets of translational control via 4E-BP1/2 in macrophages. These data are in line with numerous reports, including comparative analyses of the translatomes of WT and 4E-BP1/2 DKO mice and cells (6,52), showing that 4E-BPs do not act as general translational repressors but rather target specific subsets of mRNAs (21,(53)(54)(55)(56)(57)(58)(59). Despite the fact that eIF4E is required for cap-dependent translation of all nuclear-encoded mRNAs, some of them are particularly sensitive to eIF4E levels and/or availability and therefore are referred to as "eIF4E-sensitive" (5,31,32).…”

Section: Discussionsupporting

confidence: 92%

eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2

William

Leroux

Chaparro

et al. 2018

The Journal of Immunology

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Macrophages represent one of the first lines of defense during infections and are essential for resolution of inflammation following pathogen clearance. Rapid activation or suppression of protein synthesis via changes in translational efficiency allows cells of the immune system, including macrophages, to quickly respond to external triggers or cues without de novo mRNA synthesis. The translational repressors eIF4E-binding proteins 4E-BP1 and 4E-BP2 (4E-BP1/2) are central regulators of proinflammatory cytokine synthesis during viral and parasitic infections. However, it remains to be established whether 4E-BP1/2 play a role in translational control of anti-inflammatory responses. By comparing translational efficiencies of immune-related transcripts in macrophages from wild-type and 4E-BP1/2 double-knockout mice, we found that translation of mRNAs encoding two major regulators of inflammation, IL-10 and PG-endoperoxide synthase 2/cyclooxygenase-2, is controlled by 4E-BP1/2. Genetic deletion of 4E-BP1/2 in macrophages increased endogenous IL-10 and PGE protein synthesis in response to TLR4 stimulation and reduced their bactericidal capacity. The molecular mechanism involves enhanced anti-inflammatory gene expression (s, ,, ) owing to upregulation of IL-10-STAT3 and PGE-C/EBPβ signaling. These data provide evidence that 4E-BP1/2 limit anti-inflammatory responses in macrophages and suggest that dysregulated activity of 4E-BP1/2 might be involved in reprogramming of the translational and downstream transcriptional landscape of macrophages during pathological conditions, such as infections and cancer.

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Section: Discussionsupporting

confidence: 92%

eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2

William

Leroux

Chaparro

et al. 2018

The Journal of Immunology

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“…Often identified as CXCR5 + PD-1 + CD4 + T cells, Tfh cells are recruited into lymphoid follicles by CXCL13, the ligand for CXCR5, and promote B cell maturation in germinal centers through production of IL-21, CXCL13, IL-4, and CD40L (11). Tfh cells have been observed to be expanded in cohorts of SLE patients (9,10,12,13), and defective regulation of Tfh cells contributes to a lupus-like disease in multiple murine models ( [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

PD-1hiCXCR5– T peripheral helper cells promote B cell responses in lupus via MAF and IL-21

et al. 2019

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“…Therefore, it is reasonable to speculate that heat exposure inhibits the proliferation of IECs via the inhibition of protein turnover. mTORC1 is essential for intestinal epithelial homeostasis and regeneration (Laplante & Sabatini, 2012), depending partly on the proliferation and growth process of IECs (Fan et al, 2017;Yi et al, 2017). Previous studies have shown that inhibition of the mTORC1 signaling pathway reduces cell proliferation and blocks regeneration (Gonzalez-Estevez et al, 2012;Guo et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

mTORC1 signaling activation increases intestinal stem cell activity and promotes epithelial cell proliferation

Zhou

Huang

Qin

et al. 2019

Journal Cellular Physiology

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The crypt‐villus axis of the intestine undergoes a continuous renewal process that is driven by intestinal stem cells (ISCs). However, the homeostasis is disturbed under constant exposure to high ambient temperatures, and the precise mechanism is unclear. We found that both EdU+ and Ki67+ cell ratios were significantly reduced after exposure to 41°C, as well as the protein synthesis rate of IPEC‐J2 cells, and the expression of ubiquitin and heat shock protein 60, 70, and 90 were significantly increased. Additionally, heat exposure decreased enteroid expansion and budding efficiency, as well as induced apoptosis after 48 hr; however, no significant difference was observed in the apoptosis ratio after 24 hr. In the process of heat exposure, the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway was significantly inhibited in both IPEC‐J2 cells and enteroids. Correspondingly, treatment of IPEC‐J2 and enteroids with the mTORC1 agonist MHY1485 at 41°C significantly attenuated the inhibition of proliferation and protein synthesis, increased the ISC activity, and promoted expansion and budding of enteroid. In summary, we conclude that the mTORC1 signaling pathway regulates intestinal epithelial cell and stem cell activity during heat exposure‐induced injury.

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The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity

Cited by 50 publications

References 58 publications

eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2

eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2

PD-1hiCXCR5– T peripheral helper cells promote B cell responses in lupus via MAF and IL-21

mTORC1 signaling activation increases intestinal stem cell activity and promotes epithelial cell proliferation

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