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  • Review Article
  • Published:

Deubiquitylation and regulation of the immune response

Nature Reviews Immunology volume 8, pages 501–511 (2008)Cite this article

Key Points

  • Ubiquitylation is a reversible process that is counter-regulated by ubiquitylating and enzymes deubiquitylating enzymes (DUBs). In addition to targeting proteins for degradation by the 26S proteasome, ubiquitylation also mediates various non-degradative functions, including the regulation of protein trafficking and signal transduction.

  • DUBs form a large family of proteases that de-conjugate ubiquitin chains from target proteins and thereby regulate diverse aspects of immune function, including innate immune responses to viruses and bacteria, the development and activation of lymphocytes, and the maintenance of immunological tolerance.

  • The substrate binding of some DUBs, such as A20 and CYLD, involves specific adaptor proteins, which probably contribute to the functional diversity and specificity of the DUBs. These adaptor proteins often contain a ubiquitin-association domain that can bind to target proteins conjugated with ubiquitin chains.

  • A20 has a crucial role in the negative regulation of innate immune-receptor signalling and prevention of inflammation. A20-deficient cells have a defect in terminating the NF-κB activation signal that is elicited from the tumour-necrosis-factor receptor and Toll-like receptors, which is associated with aberrant production of pro-inflammatory mediators.

  • DUBA is a DUB that specifically regulates antiviral innate immune responses. DUBA deubiquitylates TRAF3 (tumour-necrosis factor (TNF) receptor (TNFR)-associated factor 3), an adaptor that connects the antiviral effector kinases, TBK1 (TANK-binding kinase 1) and IKKε (IκB (inhibitor of nuclear factor-κB (NF-κB)) kinase ε), to upstream signalling molecules. The DUBA-mediated deubiquitylation of TRAF3 might negatively regulate the recruitment and activation of TBK1–IKKε.

  • CYLD has a crucial role in regulating the development, activation and homeostasis of T and B cells. In addition to negatively regulating NF-κB activation, CYLD has a positive role in thymocyte T-cell receptor signalling by deubiquitylating the protein tyrosine kinase LCK.

  • Balanced events of ubiquitylation and deubiquitylation are required for the maintenance of T-cell tolerance and prevention of autoimmunity. Characterization of the DUBs that are involved in the induction of T-cell tolerance might be important for the rational design of new therapeutic approaches for treating autoimmune disorders.

Abstract

Ubiquitylation is a fundamental mechanism of signal transduction that regulates immune responses and many other biological processes. Similar to phosphorylation, ubiquitylation is a reversible process that is counter-regulated by ubiquitylating enzymes and deubiquitylating enzymes (DUBs). Despite the identification of a large number of DUBs, our knowledge of the function and activities of this family of enzymes is just starting to accumulate. As described in this Review, recent studies of several DUBs, in particular CYLD and A20, show that deubiquitylation has an important role in the regulation of both innate and adaptive immune responses.

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Figure 1: Regulation of innate immune-receptor signalling by deubiquitylating enzymes (DUBs).
Figure 2: Regulation of TCR signalling by CYLD.
Figure 3: Dual signalling functions of CYLD in B cells as indicated by studies of a natural variant, sCYLD.

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Acknowledgements

Work in my laboratory is supported by the University of Texas MD Anderson Cancer Center and the National Institutes of Health, USA, Grants R01 AI064639, R01 AI057555, R01 CA94922. I would like to thank the members of my laboratory for discussions and input, and I apologize to those authors whose work was not cited because of space limitations.

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  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, BOX 902, Houston, 77030, Texas, USA

    Shao-Cong Sun

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Glossary

26S proteasome

A giant multicatalytic protease that resides in the cytosol and nucleus. The 20S core, which contains three distinct catalytic subunits, can be appended at either end by a 19S cap or an 11S cap. The binding of two 19S caps to the 20S core forms the 26S proteasome, which degrades polyubiquitylated proteins.

E3 ubiquitin ligases

Enzymes that are required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of the ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

SH3 domains

Protein-interaction domains that are commonly found in signal-transduction molecules. They specifically interact with certain proline-containing peptides (containing either (R/K)XXPXXP or PXXPXR motifs, where X denotes any amino acid) to facilitate protein–protein interactions that are required for protein function or subcellular localization.

Small interfering RNA (siRNA)-mediated knockdown

Double-stranded RNAs (dsRNAs) with sequences that precisely match a given gene are able to 'knock down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. The two most common forms of dsRNAs used for gene silencing are short — usually 21-bp long — siRNAs or the plasmid-delivered short hairpin RNAs (shRNAs).

Yeast two-hybrid screen

A screening system for protein–protein interactions that result in the transcription of a reporter gene when a bait protein attached to a DNA-binding domain comes into contact with a prey protein bound to a transcriptional activator.

COP9 signalosome

(CSN). A multi-protein complex conserved in eukaryotic organisms that contains eight subunits, which have structural homology with the lid subunits of the 19S regulatory particle of the 26S proteasome. A prominent function of the COP9 signalosome is to regulate the activity of cullin-based E3 ubiquitin ligases, thereby modulating protein ubiquitylation and degradation.

Common cytokine-receptor γ-chain

(γc). A type I cytokine receptor chain that is shared by the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind Toll-like receptors.

Pattern-recognition receptors

(PPRs). Host receptors (such as Toll-like receptors) that can sense pathogen-associated molecular patterns and initiate signalling cascades (involving activation of nuclear factor-κB) that lead to an innate immune response.

Anergy

A state of T cells that have been stimulated through their T-cell receptors in the absence of the ligation of CD28. On restimulation, these T cells are unable to produce interleukin-2 or to proliferate, even in the presence of co-stimulatory signals.

Canonical NF-κB pathway

A typical pathway of NF-κB activation that involves phosphorylation and degradation of the prototypical NFκB inhibitor, IκBα.

Non-canonical NF-κB pathway

A pathway of NFκB activation that does not involve IκBα degradation but relies on the processing of an NF-κB precursor protein, p100, leading to nuclear translocation of the p52–RELB NFκB heterodimer.

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Sun, SC. Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8, 501–511 (2008). https://doi.org/10.1038/nri2337

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