Key Points
-
Nearly 60 CCCH zinc finger proteins have been described in humans and mice, many of which are involved in the regulation of various steps of RNA metabolism including splicing, polyadenylation, export, translation and decay.
-
Emerging evidence suggests that CCCH zinc finger proteins have a crucial role in the regulation of cytokine production, immune cell activation, immune homeostasis and antiviral innate immune responses.
-
Several CCCH zinc finger proteins — including TTP, roquin 1 and MCPIP1 — are crucial in the regulation of cytokine mRNA degradation by targeting different elements located in their 3′ untranslated regions.
-
CCCH zinc finger proteins regulate immune cell activation via multiple mechanisms, including promoting target mRNA degradation, suppressing signal transduction and repressing translation.
-
The expression and function of CCCH zinc finger proteins are regulated by multiple mechanisms, including mRNA degradation, phosphorylation and cleavage by a paracaspase MALT1.
Abstract
Nearly 60 CCCH zinc finger proteins have been identified in humans and mice. These proteins are involved in the regulation of multiple steps of RNA metabolism, including mRNA splicing, polyadenylation, transportation, translation and decay. Several CCCH zinc finger proteins, such as tristetraprolin (TTP), roquin 1 and MCPIP1 (also known as regnase 1), are crucial for many aspects of immune regulation by targeting mRNAs for degradation and modulation of signalling pathways. In this Review, we focus on the emerging roles of CCCH zinc finger proteins in the regulation of immune responses through their effects on cytokine production, immune cell activation and immune homeostasis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kafasla, P., Skliris, A. & Kontoyiannis, D. L. Post-transcriptional coordination of immunological responses by RNA-binding proteins. Nat. Immunol. 15, 492–502 (2014).
Man, K. & Kallies, A. Synchronizing transcriptional control of T cell metabolism and function. Nat. Rev. Immunol. 15, 574–584 (2015).
Carpenter, S., Ricci, E. P., Mercier, B. C., Moore, M. J. & Fitzgerald, K. A. Post-transcriptional regulation of gene expression in innate immunity. Nat. Rev. Immunol. 14, 361–376 (2014).
Hall, T. M. Multiple modes of RNA recognition by zinc finger proteins. Curr. Opin. Struct. Biol. 15, 367–373 (2005).
Liang, J., Song, W., Tromp, G., Kolattukudy, P. E. & Fu, M. Genome-wide survey and expression profiling of CCCH-zinc finger family reveals a functional module in macrophage activation. PLoS ONE 3, e2880 (2008). This study showed that there are 56 and 58 CCCH zinc finger proteins in humans and mice, respectively, through genome-wide surveys.
Gingerich, T. J. et al. Emergence and evolution of Zfp36l3. Mol. Phylogenet. Evol. 94, 518–530 (2016).
Wang, D. et al. Genome-wide analysis of CCCH zinc finger family in Arabidopsis and rice. BMC Genomics 9, 44 (2008).
Carballo, E., Lai, W. S. & Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin. Science 281, 1001–1005 (1998). This report is the first to identify TTP as a key component of a negative feedback loop that controls TNF production through a post-transcriptional mechanism.
Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005). This report is the first to identify roquin 1 as a crucial regulator of ICOS expression, T FH cell differentiation and autoimmunity.
Liang, J. et al. A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages. J. Biol. Chem. 283, 6337–6346 (2008). This report is the first to identify MCPIP1 as a negative regulator of macrophage inflammatory activation.
Matsushita, K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185–1190 (2009). These authors are the first to report that Zc3h12a acts as an endonuclease to selectively control the expression of a set of genes by promoting their mRNA decay.
Lai, W. S., Stumpo, D. J. & Blackshear, P. J. Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein. J. Biol. Chem. 265, 16556–16563 (1990).
Lai, W. S., Carballo, E., Thorn, J. M., Kennington, E. A. & Blackshear, P. J. Interactions of CCCH zinc finger proteins with mRNA: binding of tristetraprolin-related zinc finger proteins to AU-rich elements and destabilization of mRNA. J. Biol. Chem. 275, 17827–17837 (2000).
Glasmacher, E. et al. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat. Immunol. 11, 725–733 (2010).
Hudson, B. P., Martinez-Yamout, M. A., Dyson, H. J. & Wright, P. E. Recognition of the mRNA AU-rich element by the zinc finger domain of TIS11d. Nat. Struct. Mol. Biol. 11, 257–264 (2004).
Michel, S. L., Guerrerio, A. L. & Berg, J. M. Selective RNA binding by a single CCCH zinc-binding domain from Nup457 (Tristetraprolin). Biochemistry 42, 4626–4630 (2003).
Athanasopoulos, V. et al. The ROQUIN family of proteins localizes to stress granules via the ROQ domain and binds target mRNAs. FEBS J. 277, 2019–2127 (2010).
Schlundt, A. et al. Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation. Nat. Struct. Mol. Biol. 21, 671–678 (2014).
Tan, D., Zhou, M., Kiledjian, M. & Tong, L. The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double-stranded RNA. Nat. Struct. Mol. Biol. 21, 679–685 (2014).
Anderson, P. Post-transcriptional control of cytokine production. Nat. Immunol. 9, 353–359 (2008).
Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F. & Kollias, G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).
Lai, W. S. et al. Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor α mRNA. Mol. Cell. Biol. 19, 4311–4323 (1999). This study shows that CCCH zinc finger motifs of TTP are RNA-binding domains, through which TTP promotes mRNA degradation by facilitating deadenylation.
Fu, R., Olsen, M. T., Webb, K., Bennett, E. J. & Lykke-Andersen, J. Recruitment of the 4EHP–GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements. RNA 22, 373–382 (2016).
Taylor, G. A. et al. A pathogenetic role for TNFα in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4, 445–454 (1996). This study is the first to establish that TTP is a key regulator of Tnf mRNA degradation through the characterization of TTP-deficient mice.
Probert, L. et al. Dissection of the pathologies induced by transmembrane and wild-type tumor necrosis factor in transgenic mice. J. Leukoc. Biol. 59, 518–525 (1996).
Carballo, E. & Blackshear, P. J. Roles of tumor necrosis factor-α receptor subtypes in the pathogenesis of the tristetraprolin-deficiency syndrome. Blood 98, 2389–2395 (2001).
Stoecklin, G., Lu, M., Rattenbacher, B. & Moroni, C. Aconstitutive decay element promotes tumor necrosis factor α mRNA degradation via an AU-rich element-independent pathway. Mol. Cell. Biol. 23, 3506–3515 (2003).
Leppek, K. et al. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell 153, 869–881 (2013). The paper shows that roquin 1 binds a conserved stem–loop structure in the 3′ UTR of Tnf mRNA and promotes mRNA decay.
Pratama, A. et al. Roquin-2 shares functions with its paralog Roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Immunity 38, 669–680 (2013).
Nishimoto, N. Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin. Pharmacol. Ther. 87, 483–487 (2010).
Zhao, W., Liu, M., D'Silva, N. J. & Kirkwood, K. L. Tristetraprolin regulates interleukin-6 expression through p38 MAPK-dependent affinity changes with mRNA 3' untranslated region. J. Interferon Cytokine Res. 31, 629–637 (2011).
Mino, T. et al. Regnase-1 and Roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms. Cell 161, 1058–1073 (2015). This paper shows that MCPIP1 and roquin 1 regulate an overlapping set of mRNAs via a common stem–loop structure, but they target the mRNAs at different times during an immune response and in different locations within the cell.
Stoecklin, G. et al. Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. J. Biol. Chem. 283, 11689–11699 (2008).
Gaba, A. et al. Cutting edge: IL-10-mediated tristetraprolin induction is part of a feedback loop that controls macrophage STAT3 activation and cytokine production. J. Immunol. 189, 2089–2093 (2012).
Brooks, S. A. & Blackshear, P. J. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim. Biophys. Acta 1829, 666–679 (2013).
Tiedjie, C. et al. The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation. Nucleic Acids Res. 44, 7418–7440 (2016).
Sedlyarov, V. et al. Tristetraprolin binding site atlas in the macrophage transcriptome reveals a switch for inflammation resolution. Mol. Syst. Biol. 12, 868 (2016).
Huang, S. et al. Monocyte chemotactic protein-induced protein 1 and 4 form a complex but act independently in regulation of interleukin-6 mRNA degradation. J. Biol. Chem. 290, 20782–20792 (2015).
Zhang, H. et al. ZC3H12D attenuated inflammation responses by reducing mRNA stability of proinflammatory genes. Mol. Immunol. 67, 206–212 (2015).
Minagawa, K. et al. Posttranscriptional modulation of cytokine production in T cells for the regulation of excessive inflammation by TFL. J. Immunol. 192, 1512–1524 (2014).
Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).
Zhou, L. et al. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ. Res. 98, 1177–1185 (2006).
Mizgalska, D. et al. Interleukin-1-inducible MCPIP protein has structural and functional properties of RNase and participates in degradation of IL-1β mRNA. FEBS J. 276, 7386–7399 (2009).
Liang, J. et al. MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-κB signaling. J. Exp. Med. 207, 2959–2973 (2010).
Niu, J. et al. USP10 inhibits genotoxic NF-κB activation by MCPIP1-facilitated deubiquitination of NEMO. EMBO J. 32, 3206–3219 (2013).
Wang, W. et al. TRAF family member-associated NF-κB activator (TANK) inhibits genotoxic nuclear factor κB activation by facilitating deubiquitinase USP10-dependent deubiquitination of TRAF6 ligase. J. Biol. Chem. 290, 13372–13385 (2015).
Liang, J. et al. RNA-destabilizing factor tristetraprolin negatively regulates NF-κB signaling. J. Biol. Chem. 284, 29383–29390 (2009).
Schichl, Y. M., Resch, U., Hofer-Warbinek, R. & de Martin, R. Tristetraprolin impairs NF-κB/p65 nuclear translocation. J. Biol. Chem. 284, 29571–28581 (2009).
Gu, L. et al. Suppression of IL-12 production by tristetraprolin through blocking NF-κB nuclear translocation. J. Immunol. 191, 3922–3930 (2013).
Qiu, L. Q., Stumpo, D. J. & Blackshear, P. J. Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype. J. Immunol. 188, 5150–5159 (2012).
Miao, R. et al. Targeted disruption of MCPIP1/Zc3h12a results in fatal inflammatory disease. Immunol. Cell Biol. 91, 368–376 (2013).
Huang, S. et al. MCPIP1 negatively regulates Toll-like receptor 4 signaling and protects mice from LPS-induced septic shock. Cell. Signal. 25, 1228–1234 (2013).
Kawagoe, T. et al. TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat. Immunol. 10, 965–972 (2009).
Murakawa, Y. et al. RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway. Nat. Commun. 6, 7367 (2015).
Song, H. Y., Rothe, M. & Goeddel, D. V. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-κB activation. Proc. Natl Acad. Sci. USA 93, 6721–6725 (1996).
Gewurz, B. E. et al. Genome-wide siRNA screen for mediators of NF-κB activation. Proc. Natl Acad. Sci. USA 109, 2467–2472 (2012).
Uehata, T. et al. Malt1-induced cleavage of regnase-1 in CD4+ helper T cells regulates immune activation. Cell 153, 1036–1049 (2013). This study shows that MCPIP1 is essential for preventing aberrant T cell activation in a cell-autonomous manner and that the protease activity of MALT1 is crucial for controlling the mRNA stability of T cell effector genes by cleaving MCPIP1.
Hilliard, B. A. et al. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J. Clin. Invest. 110, 843–850 (2002).
Saleh, M. & Elson, C. O. Experimental inflammatory bowel disease: insights into the host microbiota dialog. Immunity 34, 293–302 (2011).
Mustelin, T. & Tasken, K. Positive and negative regulation of T-cell activation through kinases and phosphatases. Biochem. J. 371, 15–27 (2003).
Heyd, F., ten Dam, G. & Möröy, T. Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing. Nat. Immunol. 7, 859–867 (2006). This study shows that the CCCH zinc finger protein U2AF26 regulates T cell activation by controlling mRNA splicing of the transmembrane tyrosine phosphatase CD45.
Jeltsch, K. M. et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation. Nat. Immunol. 15, 1079–1089 (2014). This study shows that roquin 1 and MCPIP1 work together to repress target mRNAs and enhance T H 17 cell differentiation.
Zhou, Z. et al. MCPIP1 deficiency in mice results in severe anemia related to autoimmune mechanisms. PLoS ONE 8, e82542 (2013).
Garg, A. V. et al. MCPIP1 endoribonuclease activity negatively regulates interleukin-17-mediated signaling and inflammation. Immunity 43, 475–487 (2015).
Dhamija, S. et al. Interleukin-17 (IL-17) and IL-1 activate translation of overlapping sets of mRNAs, including that of the negative regulator of inflammation, MCPIP1. J. Biol. Chem. 288, 19250–19259 (2013).
Somma, D. et al. CIKS/DDX3X interaction controls the stability of the Zc3h12a mRNA induced by IL-17. J. Immunol. 194, 3286–3294 (2015).
Linterman, M. A. et al. Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS. Immunity 30, 228–241 (2009).
Craft, J. E. Follicular helper T cells in immunity and systemic autoimmunity. Nat. Rev. Rheumatol. 8, 337–347 (2012).
Vinuesa, C. G., Sanz, I. & Cook, M. C. Dysregulation of germinal centres in autoimmune disease. Nat. Rev. Immunol. 9, 845–857 (2009).
Yu, D. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299–303 (2007). The authors show that roquin 1 is essential for the prevention of autoimmunity by limiting Icos mRNA levels.
Bertossi, A. et al. Loss of Roquin induces early death and immune deregulation but not autoimmunity. J. Exp. Med. 208, 1749–1756 (2011).
Vogel, K. U. et al. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity 38, 655–668 (2013).
Maruyama, T. et al. Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. Sci. Signal. 7, ra8 (2014).
Zhang, Q. et al. New insights into the RNA-binding and E3 ubiquitin ligase activities of Roquins. Sci. Rep. 5, 15660 (2015). This study shows that roquin 1 and roquin 2 contain E3 ubiquitin ligase activity and bind with overlapping, but not identical, E2 enzymes to drive the assembly of polyubiquitin chains of different linkages.
Ramiscal, R. R. et al. Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation. eLife 4, e08698 (2015). This study shows that the RING domain of roquin 1 paradoxically promotes T FH cell differentiation by attenuating AMPK signalling, suggesting that roquin 1 may fine-tune the regulation of T FH cell differentiation through two different domains and two different mechanisms.
Skalniak, L. et al. Regulatory feedback loop between NF-κB and MCP-1-induced protein 1 RNase. FEBS J. 276, 5892–5905 (2009).
Iwasaki, H. et al. The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat. Immunol. 12, 1167–1175 (2011).
Skalniak, L., Koj, A. & Jura, J. Proteasome inhibitor MG-132 induces MCPIP1 expression. FEBS J. 280, 2665–2674 (2013).
Masuda, K. et al. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. Proc. Natl Acad. Sci. USA 110, 9409–9414 (2013).
Chen, Y. L. et al. Transcriptional regulation of tristetraprolin by NF-κB signaling in LPS-stimulated macrophages. Mol. Biol. Rep. 40, 2867–2877 (2013).
Brooks, S. A., Connolly, J. E. & Rigby, W. F. The role of mRNA turnover in the regulation of tristetraprolin expression: evidence for an extracellular signal-regulated kinase-specific, AU-rich element-dependent, autoregulatory pathway. J. Immunol. 172, 7263–7271 (2004).
Stoecklin, G. et al. MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J. 23, 1313–1324 (2004).
Clement, S. L., Scheckel, C., Stoecklin, G. & Lykke-Andersen, J. Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol. Cell. Biol. 31, 256–266 (2011).
Marchese, F. P. et al. MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment. J. Biol. Chem. 285, 27590–27600 (2010).
Shi, J. X., Su, X., Xu, J., Zhang, W. Y. & Shi, Y. HuR post-transcriptionally regulates TNF-α-induced IL-6 expression in human pulmonary microvascular endothelial cells mainly via tristetraprolin. Respir. Physiol. Neurobiol. 181, 154–161 (2012).
Schichl, Y. M., Resch, U., Lemberger, C. E., Stichlberger, D. & de Martin, R. Novel phosphorylation-dependent ubiquitination of tristetraprolin by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and tumor necrosis factor receptor-associated factor 2 (TRAF2). J. Biol. Chem. 286, 38466–38477 (2011).
Resch, U. et al. Polyubiquitinated tristetraprolin protects from TNF-induced, caspase-mediated apoptosis. J. Biol. Chem. 289, 25088–25100 (2014).
Ngoc, L. V. et al. Rapid proteasomal degradation of posttranscriptional regulators of the TIS11/tristetraprolin family is induced by an intrinsically unstructured region independently of ubiquitination. Mol. Cell. Biol. 34, 4315–4328 (2014).
Suzuki, T. et al. Tristetraprolin (TTP) gene polymorphisms in patients with rheumatoid arthritis and healthy individuals. Mod. Rheumatol. 18, 472–479 (2008).
Carrick, D. M. et al. Genetic variations in ZFP36 and their possible relationship to autoimmune diseases. J. Autoimmun. 26, 182–196 (2006).
Li, H., He, H., Gong, L., Fu, M. & Wang, T. T. Short communication: preferential killing of HIV latently infected CD4+ T cells by MALT1 inhibitor. AIDS Res. Hum. Retroviruses 32, 174–177 (2016).
Fontan, L. et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 22, 812–824 (2012).
Patial, S. et al. Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies. Proc. Natl Acad. Sci. USA 113, 1865–1870 (2016).
Patial, S. & Blackshear, P. J. Tristetraprolin (TTP) as a therapeutic target in inflammatory disease. Trends Pharmacol. Sci. 37, 811–821 (2016).
Rigby, R. E. & Rehwinkel, J. RNA degradation in antiviral immunity and autoimmunity. Trends Immunol. 36, 179–188 (2015).
Yokogawa, M. et al. Structural basis for the regulation of enzymatic activity of Regnase-1 by domain-domain interactions. Sci. Rep. 6, 22324 (2016).
Anderson, P. & Kedersha, N. RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat. Rev. Mol. Cell Biol. 10, 430–436 (2009).
Franks, T. M. & Lykke-Andersen, J. TTP and BRF proteins nucleate processing body formation to silence mRNAs with AU-rich elements. Genes Dev. 21, 719–735 (2007).
Fenger-Grøn, M., Fillman, C., Norrild, B. & Lykke-Andersen, J. Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping. Mol. Cell 20, 905–915 (2005).
Qi, D. et al. Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress. J. Biol. Chem. 286, 41692–41700 (2011).
Goodier, J. L. et al. The broad-spectrum antiviral protein ZAP restricts human retrotransposition. PLoS Genet. 11, e1005252 (2015).
Jing, Q. et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623–634 (2005).
Srivastava, M. et al. Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. Nat. Commun. 6, 6253 (2015).
Suzuki, H. I. et al. MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. Mol. Cell 44, 424–436 (2011).
Fabian, M. R. et al. Structural basis for the recruitment of the human CCR4-NOT deadenylase complex by tristetraprolin. Nat. Struct. Mol. Biol. 20, 735–739 (2013).
Acknowledgements
The authors thank C. J. Papasian and V. Heissmeyer for critical reading and comments on the manuscript. This work was supported by a US National Institutes of Health Grant (AI103618) and a University of Missouri Research Board Award (to M.F.) and by the Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health (to P.J.B.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
DATABASES
Supplementary information
Supplementary information S1 (table)
Human CCCH-Zinc Finger Protiens (DOC 1289 kb)
Supplementary information S2 (figure)
Categories of human CCCH-zinc finger proteins. (DOC 1682 kb)
Supplementary information S3 (box)
Antiviral function of CCCH zinc finger proteins (DOC 31 kb)
Glossary
- RNA metabolism
-
Refers to any events in the life cycle of RNA molecules, including their synthesis, folding and unfolding, modification, processing and degradation.
- Zinc finger
-
A finger-shaped fold in a protein that permits it to interact with DNA and RNA. The fold is created by the binding of specific amino acids in the protein to a zinc atom.
- AU-rich elements
-
(AREs). Found in the 3′ untranslated region (3′ UTR) of many mRNAs that encode proto-oncogenes, nuclear transcription factors and cytokines. AREs are one of the most common determinants of RNA stability in mammalian cells.
- RING finger domain
-
RING (really interesting new gene) finger domain is a protein structural domain of zinc finger type that contains a C3HC4 amino acid motif and binds two zinc cations. Many proteins containing a RING finger domain have a key role in the ubiquitylation pathway.
- Polysomes
-
Polysomes (or polyribosomes) are a cluster of ribosomes that are attached along the length of a single molecule of mRNA. Polysomes read this mRNA simultaneously, helping to synthesize the same protein at different spots on the mRNA.
- Stress granules
-
Dense aggregations in the cytosol composed of proteins and RNA molecules that appear when the cell is under stress. The RNA molecules stored in these granules are stalled translation pre-initiation complexes.
- P-bodies
-
Cytoplasmic domains that contain proteins involved in diverse post-transcriptional processes, such as mRNA degradation, nonsense-mediated mRNA decay, translational repression and RNA-mediated gene silencing.
- MicroRNA
-
(miRNA). A small, RNA molecule that regulates the expression of genes by binding to the 3′ untranslated region of specific mRNAs.
- Roquin 1san/san mice
-
Mice with a single point mutation (M199R) in the ROQ domain of the gene encoding roquin 1. These mice develop a lupus-like autoimmune phenotype, marked by enhanced numbers of T follicular helper cells and spontaneous germinal centre formation.
- MALT1
-
(Mucosa-associated lymphoid tissue lymphoma translocation protein 1). A protein of the paracaspase family that shows proteolytic activity. Since many of its substrates are involved in the regulation of inflammatory responses, the protease activity of MALT1 has emerged as an interesting therapeutic target.
- 14-3-3
-
A family of proteins that functions as adaptor molecules in protein interactions and can regulate protein localization and enzyme activity.
Rights and permissions
About this article
Cite this article
Fu, M., Blackshear, P. RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins. Nat Rev Immunol 17, 130–143 (2017). https://doi.org/10.1038/nri.2016.129
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri.2016.129
This article is cited by
-
Regulation of inflammatory diseases via the control of mRNA decay
Inflammation and Regeneration (2024)
-
Mono-ADP-ribosylation, a MARylationmultifaced modification of protein, DNA and RNA: characterizations, functions and mechanisms
Cell Death Discovery (2024)
-
Neuroprotective Effects of Melittin Against Cerebral Ischemia and Inflammatory Injury via Upregulation of MCPIP1 to Suppress NF-κB Activation In Vivo and In Vitro
Neurochemical Research (2024)
-
The Ribonuclease ZC3H12A is required for self-inflicted DNA breaks after DNA damage in small cell lung cancer cells
Cellular Oncology (2024)
-
Murine leukemia virus (MLV) P50 protein induces cell transformation via transcriptional regulatory function
Retrovirology (2023)