Deubiquitylation and regulation of the immune response

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.

Figure 1. Regulation of innate immune-receptor signalling by deubiquitylating enzymes (DUBs)

Toll-like receptors (TLRs) stimulate the K63-linked ubiquitylation of tumour-necrosis factor receptor-associated factor 6 (TRAF6) and TRAF3, which leads to the recruitment of downstream signalling molecules. a | Ubiquitylated TRAF6 recruits the IKK (IκB (inhibitor of NF-κB (nuclear factor-κB) kinase) complex (which consists of IKKα, IKKβ and IKKγ) and its activating kinase, transforming growth factor-β-activated kinase 1 (TAK1) — in association with TAK1-binding protein 1 (TAB1) and TAB2 — through the ubiquitin-binding function of IKKγ and TAB2, leading to activation of these kinases. The IKK complex phosphorylates IκB, triggering its K48-linked ubiquitylation and proteasomal degradation. Through TAX1-binding protein 1 (TAX1BP1) and A20-binding inhibitor of NF-κB 1 (ABIN1), A20 binds to and deubiquitylates TRAF6 and IKKγ, respectively, thereby negatively regulating NF-κB signalling. The role of CYLD is less clear (see main text). Deubiquitylation of IκB, which is another mechanism for the negative regulation of NF-κB, involves USP15 (ubiquitin-specific protease 15), a DUB that is associated with the COP9 signalosome (CSN). b | Ubiquitylated TRAF3 recruits the IKK-related kinases, TANK-binding kinase 1 (TBK1) and IKKε, through the adaptor protein TANK (TRAF-family-member-associated NF-κB activator). Similar to IKKγ, TANK is ubiquitylated in the signalling complex, although how the ubiquitylation of TANK contributes to the activation of TBK1 and/or IKKε is unclear. Deubiquitylation of TRAF3 is mediated by DUBA, a crucial and specific negative regulator of type I interferon (IFN) induction. c | The cytoplasmic RNA sensor, retinoic-acid-inducible gene I (RIG-I), undergoes ubiquitylation on binding to viral RNA, which is required for its association with the adaptor, IPS1 (IFNB-promoter stimulator 1), and activation of downstream signalling events. It is currently unclear which DUB regulates the deubiquitylation of RIG-I. IRF3, IFN-regulatory factor 3.

Figure 2. Regulation of TCR signalling by CYL D

Stimulation of the T-cell receptor (TCR) and CD28 induces the assembly of an intermediate signalling complex composed of CARMA1 (caspase recruitment domain (CARD) membrane-associated guanylate kinase 1), BCL-10 (B-cell lymphoma 10) and MALT1 (mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1). This core complex is also associated with the ubiquitylating enzymes UBC13 (ubiquitin-conjugating enzyme 13), UEV1A (ubiqutin-conjugating enzyme E2 variant 1A) and TRAF6 (tumour-necrosis factor receptor-associated factor 6), which catalyse the K63-linked ubiquitylation of MALT1, triggering the recruitment of IKK (IκB (inhibitor of nuclear factor-κB) kinase) and TAK1 (transforming growth factor-β-activated kinase 1) complexes. Within the CARMA1–BCL-10–MALT1 signalosome, both TAK1 and IKKγ become ubiquitylated, and these ubiquitylation events are important for triggering the catalytic activity of TAK1 and the IKK complex, respectively. CYLD is an essential deubiquitylating enzyme (DUB) that prevents the spontaneous ubiquitylation and activation of TAK1. CYLD deficiency causes constitutive activation of TAK1 and its downstream IKK and JNK (JUN N-terminal kinase) signalling pathways. CYLD positively regulates the TCR-proximal kinase LCK in thymocytes. Whether this function of CYLD is retained in peripheral T cells is not clear. AP1, activator protein 1; TAB, TAK1-binding protein.

Figure 3. Dual signalling functions of CYL D in B cells as indicated by studies of a natural variant, sCYL D

a | B-cell receptor (BCR) signalling activates the inhibitor of nuclear factor-κB (NF-κB) kinase (IKK)–NF-κB signalling pathway through the CARMA1–BCL-10–MALT1 signalosome. Although the precise targets of CYLD in B cells remain unclear, CYLD negatively regulates the IKK complex and NF-κB. Based on recent work on a short isoform of CYLD (sCYLD), it is conceivable that CYLD might also have a positive signalling target, possibly one of the SRC kinases (LYN or SYK) as their T-cell homologue, LCK, is positively regulated by CYLD. b | sCYLD is encoded by a natural splicing variant of the CYLD gene that lacks exons 7 and 8. sCYLD does not contain the TRAF2- and IKKγ-binding domains that are required for negative regulation of NF-κB, but it retains the deubiquitylating enzyme (DUB) activity. One implication is that sCYLD is defective in binding to its negative targets (such as IKKγ) but remains effective towards its positive targets, which would explain the B-cell hyper-activation in mice expressing sCYLD. BCL-10, B-cell lymphoma 10; CARMA1, caspase recruitment domain (CARD) membrane-associated guanylate kinase 1; Cap-Gly, cytoskeleton-associated protein glycine-rich domain; MALT1, mucosa-associated lymphoid-tissue lymphoma-translocation gene 1.