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Immunology Letters 160 (2014) 102–103

Contents lists available at ScienceDirect

Immunology Letters

j our na l ho me page: www.elsev ier .com/ locate / immlet

and overexpression of BCL10, a caspase recruitment domain-containing gene,

etter to the Editor

999–2014: 15 years of BCL10

In fact, starting from the study of this seemingly small and cryp-ic molecule, subsequent years have witnessed profound advancesn our comprehension of the mechanisms that control activationf lymphocytes, and how their deregulation is both responsibleor pathological immunodeficiencies and lymphoproliferative dis-rders.

BCL10 was identified in the late 90s, at the end of the reduc-ionistic decade that had led to the clarification of the molecular

echanisms that control the apoptotic cascade following stimu-ation of death receptors [1–7]. Despite the presence of a caspaseecruiting domain (CARD) in its sequence, it soon became appar-nt, however, that BCL10 does not participate in the regulationf apoptotic pathways, but rather is a critical activator of NF-�B,

transcription factor essential for proper initiation and progres-ion of a normal immune response. NF-�B, in fact, transcribes genehat positively regulate survival, proliferation and differentiationf lymphoid cells. The deregulated activity of NF-�B is responsibleor the transforming potential of BCL10.

The generation of a murine strain genetically targeted in theocus encoding for BCL10 enlightened the functional role playedy this protein [8]. BCL10−/− mice are in fact severely immunode-cient, being their lymphocytes defective in activation followingntigen receptor stimulation. Whereas Ca2+ signaling and MAPKctivation are normal in BCL10−/− mutant lymphocytes, antigeneceptor-induced NF-�B activation is absent, and this deficiencys sufficient to cause severe immunodeficiency [8]. Intriguingly,n addition to the immunological disorders, about one-third ofCL10−/− embryos developed severe exencephaly that led tombryonic lethality.

But how does BCL10 work? The last fifteen years of intenseesearch have established that BCL10, in transducing signals fromhe antigen receptor, participates to the formation of a molec-lar complex that also includes CARMA1 and MALT1 proteins,hereby named CBM complex [9]. CARMA1 is a member of a fam-ly of three scaffolding proteins (CARMA1–3) able to associateCL10 through an homophilic interaction between the correspond-

ng CARD domains, and to cooperate with BCL10 in activatingF-�B [10,11]. Of the three CARMA proteins, CARMA1 is theost abundantly expressed in lymphoid tissues and, similarly to

CL10, it plays an indispensable role in NF-�B activation follow-ng antigen receptor stimulation on lymphocyte [12–14]. FollowingCR stimulation, CARMA1 is phosphorylated by PKC�, and thishosphorylation results in a conformational change that enableARMA1 to associate with BCL10 [15–17] and MALT1, a proteinith paracaspase proteolitic activity required for NF-�B activa-

ion also involved in MALT lymphomas [18]. Correct assembly ofhe CBM complex is believed to be anessential step for triggeringhe subsequent events that lead to activation of NF-�B follow-ng antigen receptor stimulation. Thus, the CBM complex would

ttp://dx.doi.org/10.1016/j.imlet.2014.02.002165-2478/© 2014 Elsevier B.V. All rights reserved.

function as a scaffold structure dedicated to the ordered recruit-ment of signal amplifier/transducer molecules, which eventuallyfinalize activation of NF-�B.

However, the exact mechanism by which the CBM complexactivates NF-�B is still unknown. The CBM complex most likelyserves as a molecular platform to recruit signaling componentsresponsible for K63-linked polyubiquitination of NEMO, a regula-tory subunit of the IKK complex that is responsible for activationof NF-�B [19,20]. Evidence for scaffolding filamentous assem-bly structures involving BCL10 and CARMA1 first came from cellmicroscopy observations, subsequently confirmed by structuralstudies [21,22]. Indeed, activation of the IKK complex is notonly dependent on IKK phosphorylation but also on CARMA1-dependent recruitment and non-degradative ubiquitination ofNEMO [19,20,23]. The importance of the ubiquitination events forthe CBM-dependent activation of NF-�B is furthermore underlinedby the fact that enzymatic deubiquitinases such as A20 significantlyinhibits activation of NF-�B mediated by the CBM complex [24].

Given the critical role for CBM proteins and the NF-�B pathwayin the control of lymphocyte survival and proliferation, it is not sur-prising to find altered expression and/or function of CBM proteinsin specific types of B-cell lymphomas. As mentioned before, bothBCL10 and MALT1 were identified because of their involvement inMALT B-cell lymphomas. More importantly, screening of patientsamples performed independently by six groups has revealed thatCARMA1 is mutated in about 10% of systemic and 16% of primarycentral nervous system diffuse large B cell lymphomas, the mostcommon type of non-Hodgkin’s lymphoma. Significantly, in thesescreenings the A20 deubiquitinase was also found to be one of themost mutated gene [25,26].

In conclusion, after fifteen years, we certainly have a clearer andmore complete understanding of BCL10 with respect to its functionand to the molecular mechanisms in which it takes part. Certainly,some aspects of BCL10 are still covered by dense mystery: for exam-ple, what exactly does BCL10 do in the CBM complex? And again:how BCL10 relates to the non-degradative ubquitination events?And finally: what is the role of BCL10 in the development of thenervous system?

But for all this there is still time, for now Happy Birthday, BCL10,enjoy your first fifteen years!

References

[1] Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M, et al. Bcl10is involved in t(1;14)(p22;q32) of MALT B cell lymphomas and mutated inmultiple tumor types. Cell 1999;96:35–45.

[2] Zhang Q, Siebert R, Yan M, Hinzmann B, Cui X, Xue L, et al. Inactivating mutation

in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 1999;22:63–8.[3] Costanzo A, Guiet C, Vito P. c-E10 is a caspase-recruiting domain-containing

protein that interacts with components of death receptors signaling pathwayand activates nuclear factor-kappaB. J Biol Chem 1999;274:20127–32.

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Letter to the Editor / Immun

[4] Koseki T, Inohara N, Chen S, Carrio R, Merino J, Hottiger MO, et al. CIPER, a novelNF kappaB-activating protein containing a caspase recruitment domain withhomology to Herpesvirus-2 protein E10. J Biol Chem 1999;274:9955–61.

[5] Srinivasula SM, Ahmad M, Lin JH, Poyet JL, Fernandes-Alnemri T, Tsichlis PN,et al. CLAP, a novel caspase recruitment domain-containing protein in thetumor necrosis factor receptor pathway, regulates NF-kappaB activation andapoptosis. J Biol Chem 1999;274:17946–54.

[6] Thome M, Martinon F, Hofmann K, Rubio V, Steiner V, Schneider P, et al.Equine herpesvirus-2 E10 gene product, but not its cellular homologue, acti-vates NF-kappaB transcription factor and c-Jun N-terminal kinase. J Biol Chem1999;274:9962–8.

[7] Yan M, Lee J, Schilbach S, Goddard A, Dixit V. mE10, a novel caspase recruitmentdomain-containing proapoptotic molecule. J Biol Chem 1999;274:10287–92.

[8] Ruland J, Duncan GS, Elia A, del Barco Barrantes I, Nguyen L, Plyte S, et al. Bcl10is a positive regulator of antigen receptor-induced activation of NF-kappaB andneural tube closure. Cell 2001;104:33–42.

[9] Thome M, Charton JE, Pelzer C, Hailfinger S. Antigen receptor signaling toNF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol2010;2(9):a003004.

10] Bertin J, Wang L, Guo Y, Jacobson MD, Poyet JL, Srinivasula SM, et al. CARD11 andCARD14 are novel caspase recruitment domain (CARD)/membrane-associatedguanylate kinase (MAGUK) family members that interact with BCL10 and acti-vate NF-kappa B. J Biol Chem 2001;276:11877–82.

11] Gaide O, Favier B, Legler DF, Bonnet D, Brissoni B, Valitutti S, et al. CARMA1 isa critical lipid raft-associated regulator of TCR-induced NF-kappa B activation.Nat Immunol 2002;3:836–43.

12] Hara H, Wada T, Bakal C, Kozieradzki I, Suzuki S, Suzuki N, et al. The MAGUKfamily protein CARD11 is essential for lymphocyte activation. Immunity2003;18:763–75.

13] Egawa T, Albrecht B, Favier B, Sunshine MJ, Mirchandani K, O’Brien W, et al.Requirement for CARMA1 in antigen receptor-induced NF-kappa B activationand lymphocyte proliferation. Curr Biol 2003;13:1252–8.

14] Newton K, Dixit V. Mice lacking the CARD of CARMA1 exhibit defective B lym-phocyte development and impaired proliferation of their B and T lymphocytes.Curr Biol 2003;13:1247–51.

15] Matsumoto R, Wang D, Blonska M, Li H, Kobayashi M, Pappu B, et al. Phosphor-ylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaBactivation. Immunity 2005;23:575–85.

16] Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-García ME,Ovechkina YL, et al. Phosphorylation of the CARMA1 linker controls NF-kappaBactivation. Immunity 2005;23:561–74.

17] McCully RR, Pomerantz JL. The protein kinase C-responsive inhibitory domainof CARD11 functions in NF-kappaB activation to regulate the association of

multiple signaling cofactors that differentially depend on Bcl10 and MALT1 forassociation. Mol Cell Biol 2008;28:5668–86.

18] Ruefli-Brasse AA, French DM, Dixit VM. Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase. Science2003;302:1581–4.

etters 160 (2014) 102–103 103

19] Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ. The TRAF6 ubiquitin ligase and TAK1kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell2004;14:289–301.

20] Wu CJ, Ashwell JD. NEMO recognition of ubiquitinated Bcl10 is requiredfor T cell receptor-mediated NF-kappaB activation. Proc Natl Acad Sci USA2008;105:3023–8.

21] Guiet C, Vito P. Caspase recruitment domain (CARD)-dependent cytoplas-mic filaments mediate bcl10-induced NF-kappaB activation. J Cell Biol2000;148(6):1131–40.

22] Qiao Q, Yang C, Zheng C, Fontán L, David L, Yu X, et al. Structural architectureof the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentousassembly. Mol Cell 2013;51(6):766–79.

23] Stilo R, Liguoro D, Di Jeso B, Formisano S, Consiglio E, Leonardi A, et al. Phys-ical and functional interaction of CARMA1 and CARMA 3 with Ikappa kinasegamma-NF-kappaB essential modulator. J Biol Chem 2004;279:34323–31.

24] Stilo R, Varricchio E, Liguoro D, Leonardi A, Vito P. A20 is a negative regulator ofBCL10- and CARMA3-mediated activation of NF-kappaB. J Cell Sci 2008;121(Pt8):1165–71.

25] Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW, et al. Onco-genic CARD11 mutations in human diffuse large B cell lymphoma. Science2008;319:1676–9.

26] Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, et al.Mutations of multiple genes cause deregulation of NF-kappaB in diffuse largeB-cell lymphoma. Nature 2009;459:717–21.

Pasquale Vito a,b,∗

Romania Stilo a,b

a Biogem Consortium, Via Camporeale,83031 Ariano Irpino, Italy

b Dipartimento di Scienze e Tecnologie, Universitàdegli Studi del Sannio, Via Port”Arsa 11,

82100 Benevento, Italy

∗ Corresponding author at: Dipartimento di Scienzee Tecnologie, Università degli Studi del Sannio,

Via Port’Arsa 11, 82100 Benevento, Italy.Tel.: +39 0824305105.

E-mail address: vito@unisannio.it (P. Vito)

4 February 2014

Available online 18 February 2014