RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

Fu, Mingui; Blackshear, Perry J.

doi:10.1038/nri.2016.129

Cited by 268 publications

(260 citation statements)

References 107 publications

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“…Together, these results indicate that Klf4 regulates the expression of MCPIP1, which then translocates to the cytoplasm to regulate NF-κB. [12,24]. In line with this model, we found that exposure to lipopolysaccharide dramatically enhanced MCPIP1 expression in macrophages, as shown in Figure 4 A to C, especially at 2 to 6 hours after exposure.…”

Section: Klf4 Mediates Mcpip1 Transcription To Regulate Nf-κbsupporting

confidence: 74%

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Jia

Han

et al. 2018

Cell Physiol Biochem

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Background/Aims: Inflammation is an essential component of innate immunity against pathogens, but is tightly regulated, such as by Krüppel-like factor 4 (Klf4), to prevent injury. Klf4 also regulates macrophage polarization, although the mechanisms underlying both functions are poorly understood. The aim of this study was to investigate whether and how Klf4 prevents unregulated inflammation. Methods: The bone marrow-derived macrophages and RAW264.7 cell line were used. Quantitative real-time PCR was used to determine inflammatory cytokines (IL-1β, TNF-α, IL-6 and MCP-1), Klf4 and MCPIP1 transcript levels. Extraction of nuclear and cytoplasmic proteins and Immunoblotting were used to determine Klf4, MCPIP1, relative kinases from NF-κB pathway and K63-linked polyubiquitins expression in nucleus and cytoplasm separately. Dual luciferase reporter assay was used to analyze whether Klf4 mediate MCPIP1 transcription. Immunoprecipitation was used to determine the protein interaction among Klf4, MCPIP1, TRAF6 and K63-linked polyubiquitins. Secretion of IL-1β and TNF-α into sera in mice was measured by Enzyme-linked immunosorbent assay. Results: We found that exposure to lipopolysaccharides suppresses Klf4 expression, even as it induces release of pro-inflammatory cytokines. Strikingly, Klf4 overexpression significantly lowered cytokine secretion and NF-κB signaling in the cytoplasm following exposure to lipopolysaccharide, even though Klf4 was exclusively nuclear. The cytoplasmic effects are likely mediated by MCP-1 induced protein 1 (MCPIP1), a deubiquitinase and a key modulator of inflammation that accumulates both in the nucleus and cytoplasm in response to Klf4. Indeed, binding between MCPIP1 and K63 polyubiquitins is attenuated in macrophages overexpressing Klf4, suggesting that MCPIP1 is an intermediator induced by Klf4 in the nucleus to remove K63 polyubiquitins from TRAF6 in the cytoplasm, and thereby impede NF-κB and inflammatory signaling. Importantly, Klf4 overexpression in mice alleviated sepsis symptoms following exposure to lipopolysaccharides. Conclusion: The data highlight Klf4 as an essential MCPIP1-dependent modulator of innate immunity that protects against excessive and self-destructive inflammation.

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Section: Klf4 Mediates Mcpip1 Transcription To Regulate Nf-κbsupporting

confidence: 74%

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Jia

Han

et al. 2018

Cell Physiol Biochem

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“…[6] Often referred to as "CCCH" type ZF,t hese "non-classical" ZFs are involved in RNA regulation. [6] Often referred to as "CCCH" type ZF,t hese "non-classical" ZFs are involved in RNA regulation.…”

Section: Introductionmentioning

confidence: 99%

“…[1a] During inflammation, cytokines (e.g.,T NF-a)s timulate signaling pathways to produce more cytokines. [6] This property has led to TTP being dubbed a" master regulator" of inflammation. The biochemical mechanism of action involves recognition of specificA U-rich cytokinem RNA sequences, throughT TP'st wo Cys 3 His ZF domains ( Figure 1A,B).…”

Section: Introductionmentioning

confidence: 99%

Role of Gold in Inflammation and Tristetraprolin Activity

Neu

et al. 2020

Chemistry A European J

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The zinc finger protein tristetraprolin (TTP) regulates inflammation by downregulatingc ytokinem RNAs. Misregulation resultsi na rthritis, sepsis and cancer,a nd there is an interesti nm odulating TTP activity with exogenous agents. Gold hasa nti-inflammatory properties and has recently been shown to modulate the signaling pathway that produces TTP,s uggesting that TTP may be at arget of gold. The reactivity of [Au III (terpy)Cl]Cl 2 with TTPw as investigated by UV/Vis spectroscopy,s pin-filter inductively coupled plasma mass spectrometry,X -ray absorption spectroscopy and native electrospray ionization mass spectrometry.A u III was found to replace zinc in the protein active site in the reduced Au I form, with the Au I ion coordinated to two cysteine residues in al inear geometry.T he replacement of Zn II with Au I resultsi nl oss of both secondary structure and RNA binding function. In contrast, when Zn II TTP is boundt oi ts RNA target, no replacement of Zn II with Au I is observed, even in the presence of excessA u III terpy.T his discovery of differential reactivity of gold with TTP versus TTP/RNA offers ap otentials trategy for selectivet argeting with gold complexest oc ontroli nflammation.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.org/10.1002/chem.201904837.Scheme1.Cartoon diagram of role of TTP in TNF-a signaling. TTP (in yellow) regulates TNF-a by binding to and degrading its mRNA as part of the NF-kBs ignaling pathway.

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“…CCCH-type zinc fingers are known involved in RNA binding and RNA metabolism (Amann et al 2003; Murn et al 2016; Fu and Blackshear 2017). Here we report the solution structure of METTL3 zinc finger domain (ZFD) that comprises two tandem zinc fingers.…”

Section: Introductionmentioning

confidence: 99%

Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferase

et al. 2018

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N-methyladenosine (mA), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity. Here we present the solution structure for the zinc finger domain (ZFD) of METTL3, the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14. We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3' consensus sequence, but does not to one without. The ZFD thus serves as the target recognition domain, a structural feature previously shown for DNA methyltransferases, and cooperates with the MTDs of METTL3-METTL14 for catalysis. However, the interaction between the ZFD and the specific RNA is extremely weak, with the binding affinity at several hundred micromolar under physiological conditions. The ZFD contains two CCCH-type zinc fingers connected by an anti-parallel β-sheet. Mutational analysis and NMR titrations have mapped the functional interface to a contiguous surface. As a division of labor, the RNA-binding interface comprises basic residues from zinc finger 1 and hydrophobic residues from β-sheet and zinc finger 2. Further we show that the linker between the ZFD and MTD of METTL3 is flexible but partially folded, which may permit the cooperation between the two domains during catalysis. Together, the structural characterization of METTL3 ZFD paves the way to elucidate the atomic details of the entire process of RNA mA modification.

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RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins

Cited by 268 publications

References 107 publications

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Role of Gold in Inflammation and Tristetraprolin Activity

Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferase

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