RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

McKelvey, Alison C.; Dunn, Sarah R.; Evankovich, John; Londino, J.D.; Bednash, Joseph S.; Zhang, Yingze; McVerry, Bryan J.; Liu, Yuan; Chen, Bill B.

doi:10.7554/elife.18496

Cited by 19 publications

(17 citation statements)

References 53 publications

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“…Furthermore, Trim21 À/À BMDMs were hyporesponsive to TLR2 stimulation by both the synthetic ligand PAM3CSK4 and M. bovis BCG, indicating that TRIM21 also plays an important role in response to more complex stimuli. 30 The change in cytokine production after TLR2 activation of Trim21 À/À BMDMs is of a similar moderate magnitude to changes reported after knockdown of other E3 ligases, including TRIM13 26 and CHIP. Trim21 À/À bone-marrow-derived macrophages (BMDMs) are hyporesponsive to Mycobacterium bovis Bacillus Calmette-Gu erin (BCG).…”

Section: Discussionsupporting

confidence: 57%

“…Interestingly, a TLR2-specific E3 ubiquitin ligase (PPP1R11) has recently been described, demonstrating that TLR2 signaling can directly be controlled by ubiquitination. 30 The change in cytokine production after TLR2 activation of Trim21 À/À BMDMs is of a similar moderate magnitude to changes reported after knockdown of other E3 ligases, including TRIM13 26 and CHIP. 27 This is expected, because E3 ligases are modulators of signaling rather than necessary components of the signaling pathways.…”

Section: Discussionsupporting

confidence: 57%

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TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

et al. 2019

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TRIM21 is an interferon-stimulated E3 ligase that controls the activity of pattern-recognition signaling via ubiquitination of interferon regulatory factors and DDX41. Previous studies on the role of TRIM21 in innate immune responses have yielded contradictory results, suggesting that the role of TRIM21 is cell specific. Here, we report that bone-marrow-derived macrophages (BMDMs) generated from Trim21 À/À mice have reduced expression of mature macrophage markers. Reflecting their reduced differentiation in response to macrophage colony-stimulating factor (M-CSF), Trim21 À/À BMDMs had decreased expression of M-CSF signature genes. Although Trim21 À/À BMDMs responded normally to Toll-like receptor 9 (TLR9) activation, they produced lower levels of pro-inflammatory cytokines in response to the TLR2 agonist PAM3CSK4. In line with this, the response to infection with the Bacillus Calmette-Gu erin strain of Mycobacterium bovis was also diminished in Trim21 À/À BMDMs. Our results indicate that TRIM21 controls responses to TLR2 agonists.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionsupporting

confidence: 57%

TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages

et al. 2019

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“…Owing to the established role of ligand binding in the ubiquitination and degradation of membrane receptors, we examined whether ligand stimulation altered IFNGR1 stability [10,17,28,29]. Several studies have previously investigated the role of IFN-γ binding on receptor stability with conflicting results [30–32].…”

Section: Discussionmentioning

confidence: 99%

Post-translational modification of the interferon-gamma receptor alters its stability and signaling

Londino

Gulick

Suber

et al. 2017

Biochemical Journal

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The IFN gamma receptor 1 (IFNGR1) binds IFN-γ and activates gene transcription path ways crucial for controlling bacterial and viral infections. Although decreases in IFNGR1 surface levels have been demonstrated to inhibit IFN-γ signaling, little is known regarding the molecular mechanisms controlling receptor stability. Here, we show in epithelial and monocytic cell lines that IFNGR1 displays K48 polyubiquitination, is proteasomally degraded, and harbors three ubiquitin acceptor sites at K277, K279, and K285. Inhibition of glycogen synthase kinase 3 beta (GSK3β) destabilized IFNGR1 while overexpression of GSK3β increased receptor stability. We identified critical serine and threonine residues juxtaposed to ubiquitin acceptor sites that impacted IFNGR1 stability. In CRISPR–Cas9 IFNGR1 generated knockout cell lines, cellular expression of IFNGR1 plasmids encoding ubiquitin acceptor site mutations demonstrated significantly impaired STAT1 phosphoryl ation and decreased STAT1-dependent gene induction. Thus, IFNGR1 undergoes rapid site-specific polyubiquitination, a process modulated by GSK3β. Ubiquitination appears to be necessary for efficient IFNGR1-dependent gamma gene induction and represents a relatively uncharacterized regulatory mechanism for this receptor.

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“…inflammation and injury. Previous research suggests that the stability of key proteins that regulate pulmonary inflammation influences lung pathology, such as the ubiquitin proteasome-dependent degradation of TLR2, PIAS1, and FBXL2 (23)(24)(25). To better understand the role of SOCS2 in pulmonary inflammation, we investigated the regulation of SOCS2 protein stability and its effects on pulmonary inflammation.…”

Section: Introductionmentioning

confidence: 99%