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

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.

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Figure 1: Schematic structures of human tristetraprolin (TTP), roquin and monocyte chemotactic protein-induced protein (MCPIP) protein families.
Figure 2: Regulation of cytokine production by CCCH zinc finger proteins.
Figure 3: Regulation of macrophage activation by CCCH zinc finger proteins.
Figure 4: Roquin 1 and roquin 2 regulate TFH cell differentiation.
Figure 5: Expression and function of CCCH zinc finger proteins are regulated by multiple mechanisms.

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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.).

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Correspondence to Mingui Fu.

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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.

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Fu, M., Blackshear, P. RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins. Nat Rev Immunol 17, 130–143 (2017) doi:10.1038/nri.2016.129

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