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Cellular Immunology Ubiquitination and Phosphorylation of The Cellular Immunology 340 (2019) 103877 Contents lists available at ScienceDirect Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm Review article Ubiquitination and phosphorylation of the CARD11-BCL10-MALT1 T signalosome in T cells ⁎ Marie Lorka,b, Jens Staala,b, Rudi Beyaerta,b, a Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium b Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, VIB, Ghent, Belgium ARTICLE INFO ABSTRACT Keywords: Antigen receptor-induced signaling plays an important role in inflammation and immunity. Formation ofa T cells CARD11-BCL10-MALT1 (CBM) signaling complex is a key event in T- and B cell receptor-induced gene ex- Lymphocytes pression by regulating NF-κB activation and mRNA stability. Deregulated CARD11, BCL10 or MALT1 expression CARD11 or CBM signaling have been associated with immunodeficiency, autoimmunity and cancer, indicating that CBM MALT1 formation and function have to be tightly regulated. Over the past years great progress has been made in de- BCL10 ciphering the molecular mechanisms of assembly and disassembly of the CBM complex. In this context, several Ubiquitin Phosphorylation posttranslational modifications play an indispensable role in regulating CBM function and downstream signal Inflammation transduction. In this review we summarize how the different CBM components as well as their interplay are Immunity regulated by protein ubiquitination and phosphorylation in the context of T cell receptor signaling. NF-κB Abbreviations: ABC-DLBCL, activated-B-Cell-like diffuse large B cell lymphoma; ADAP, adhesion and degranulation-promoting adapter protein; AIP, AHreceptor- interacting protein; Akt, protein kinase B; AP-1, activator protein 1; API2, apoptosis Inhibitor 2; ATG12, autophagy related 12; BCL10, B-cell lymphoma/leukemia 10; BCR, B cell receptor; BENTA, B cell expansion with NF-κB and T cell anergy; βTRCP, β-transducing repeat-containing protein; BIR, baculoviral inhibitor of apoptosis (IAP)-repeats; BIRC3, baculoviral inhibitor of apoptosis (IAP) repeat-containing 3; CaMK, Ca2+/calmodulin-dependent kinase; CARD, caspase recruitment domain; CARD11, caspase recruitment domain family member 11; Carma, caspase recruitment domain (CARD)-containing MAGUK proteins; Cbl-b, casitas B-lineage lym- phoma proto-oncogene-b; CBM, CARD11-BCL10-MALT1 complex; cIAP, cellular inhibitor of apoptosis; CID, combined immunodeficiency; CK1α, casein kinase 1α; CYLD, cylindromatosis; DAG, diacylglycerol; DUB, deubiquitinase; Erk1, extracellular signal-regulated kinase 1; FOXP3, forkhead box P3; GSK3β, glycogen synthase kinase 3 beta; GST, glutathione S-transferase; GUK, guanylate kinase-like; HECT, homologous to the E6AP carboxyl terminus; HOIL-1, heme-oxidized IRP2 ligase-1; HOIP, heme-oxidized IRP2 ligase-1 (HOIL-1)-Interacting Protein; HPK1, hematopoietic progenitor kinase 1; Ig, immunoglobulin; IKK, IκB kinase; IP3, inositol trisphosphate; ITAM, immunoreceptor tyrosine-based activation motif; ITCH, itchy E3 ubiquitin protein ligase; IκBα, inhibitor of NF-κB α; JNK, c-jun N-terminal kinase; LAMP1, lysosomal-associated membrane protein 1; LAT, linker for the activation of T cells; LC3, microtubule-associated protein 1A/1B-light chain 3; Lck, lymphocyte cell-specific protein-tyrosine kinase; LUBAC, linear ubiquitin chain assembly complex; MAGUK, membrane-associated guanylate kinase; MALT1,mu- cosa-associated lymphoid tissue lymphoma translocation protein 1; MAPK, mitogen-associated protein kinase; MHC, major histocompatibility complex; MIB2, mindbomb E3 ubiquitin protein ligase 2; NEDD, neuronal precursor cell-expressed developmentally downregulated; NEMO, NF-κB essential modulator; NF-AT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; NKT, natural killer T cell; NZF, Npl4 zinc finger domain; p62, sequestosome 1; PDZ, postsynaptic density 95/disc large/zona occludens 1 domain; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5 bisphosphate; PKC, protein kinase C; PLCγ, phospholipase C; PMA, phorbol 12-myristate 13-acetate; POLKADOTS, punctate and oligomeric killing or activating domains transducing signals; PP2A, protein phosphatase 2; PRD, PKC regulated domain; PTM, posttranslational modification; RIPK2, receptor interacting serine/threonine kinase 2; RNF, ring finger protein; SH3, Src homology3; SHARPIN, SHANK associated RH domain interactor; SLP-76, Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa; STUB1, Stress Induced Phosphoprotein 1 (STIP1) homology and U-box containing protein 1; SUMO, Small ubiquitin-like modifier; TAB2/3, TAK1-binding proteins 2 and 3; TAK1, Transforming growth factor beta (TGFβ)-activated kinase 1; TBK1, TRAF Family Member Associated NF-κB Activator (TANK) binding kinase 1; TCR, T cell receptor; TRAF6, tumor necrosis factor (TNF) receptor-associated factor 6; T6BM, TRAF6-binding motif; UBAN, ubiquitin binding in A20 binding inhibitor of NF-κB (ABIN) and NEMO; Ubc13, ubiquitin conjugating enzyme E2N; UBD, ubiquitin binding domain; Uev1A, ubiquitin-conjugating enzyme E2 variant 1; USP, ubiquitin-specific protease; ZAP-70, ζ-associated protein of 70 kDa ⁎ Corresponding author at: Center for Inflammation Research, VIB-Ghent University, Technologiepark 927, B-9052 Ghent, Belgium. E-mail address: [email protected] (R. Beyaert). https://doi.org/10.1016/j.cellimm.2018.11.001 Received 21 August 2018; Accepted 2 November 2018 Available online 01 December 2018 0008-8749/ © 2018 Elsevier Inc. All rights reserved. M. Lork, et al. Cellular Immunology 340 (2019) 103877 1. Introduction the covalent attachment of ubiquitin to the side chain of a lysine (K) residue in a target protein requires the concerted action of three dif- The immune system is a complex interplay between different cells, ferent enzymes: an ubiquitin-activating enzyme (E1), an ubiquitin tissues and organs, developed to protect the organism from invading conjugating enzyme (E2), and an ubiquitin ligase enzyme (E3) (Fig. 1). threats. As a signaling system, the immune system is facing a unique Ubiquitin itself contains seven lysine residues that can also serve as and interesting challenge in that pathogens typically have much shorter ubiquitin acceptor sites, allowing the formation of structurally different generation times and consequently evolve much faster than their hosts, types of polyubiquitin chains (K6, K11, K27, K29, K33, K48 and K63). which means that the immune system needs to be vigilant and re- In addition, a ubiquitin molecule can be attached to the N-terminal sponsive to novel threats. At the same time is a poorly regulated im- methionine (M1) of the proximal ubiquitin residue, leading to the for- mune response detrimental to the organism, which means that an ef- mation of linear ubiquitin or M1 chains [4]. Different types of poly- fective negative regulation of immune responses is also important. ubiquitination form a kind of ubiquitin code that is recognized by Physical barriers and the innate immune system serve as the first lines specific ubiquitin-binding domain (UBD)-containing proteins that of defense. Conserved components of pathogens are sensed by pattern mediate downstream signaling. Ubiquitin can also be attached to serine, recognition receptors on cells, which elicit an innate immune response threonine or cysteine residues, but they are less stable and to date very by production of antimicrobial factors and inflammatory mediators. little is known about these modifications [5]. The ubiquitin code proved Innate immunity also regulates the recruitment and activation of to be even more complex when mixed chain types such as M1/K63 and adaptive immune cells [1]. Adaptive immunity depends on T and B K48/K63 hybrid chains were identified [6,7]. There are also hybrid lymphocytes carrying highly specific antigen-recognition receptors, the chains of ubiquitin-like modifications and ubiquitin such as ubiquitin- B cell receptor (BCR) and T cell receptor (TCR). Once activated, B cells SUMO or ubiquitin-NEDD8 hybrid conjugates. Furthermore, ubiquitin produce antibodies against pathogens mediating the humoral immune itself can be subject to PTMs, for example acetylation of its lysine re- response. CD4 T cells help B cells in the humoral response, while CD8 T sidues or phosphorylation on serine (S), threonine (T) or tyrosine (Y) cells and natural killer cells play a role in the cell-mediated immune residues. In particular S65 phosphorylation has been studied ex- response to e.g. kill virus infected cells or cancer cells [2]. tensively in the context of mitophagy [8]. Each of these ubiquitin Immune cell signal transduction needs to be tightly regulated, modifications can alter the charge and surface properties of ubiquitin which highly depends on posttranslational modifications (PTMs). There and can hence dramatically affect signaling outcome. While K48-linked is a wide range of PTMs like acetylation, lipid conjugations, oxidation, polyubiquitination mainly targets proteins for proteasomal degrada- phosphorylation, proteolytic processing, ubiquitination and ubiquitin- tion, K63- and M1-linked polyubiquitin chains can regulate protein like modification, which all can play a direct role in signal transduction, activity, protein subcellular localization or protein-protein interaction but possibly also serve as “memory” to influence or cross-talk with in various signaling pathways [9]. Like phosphorylation, ubiquitination other signaling events. This complex change in the
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