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B-cell CLL/Lymphoma 10 (BCL10) Is Required for NF-κB Production by Both Canonical and Noncanonical Pathways and for NF-κB-inducing Kinase (NIK) Phosphorylation*

Open AccessPublished:November 06, 2009DOI:https://doi.org/10.1074/jbc.M109.050815
      B-cell CLL/lymphoma 10 (BCL10), the caspase recruitment domain (CARD)-containing protein involved in the etiology of the mucosa-associated lymphoid tissue (MALT) lymphomas, has been implicated in inflammatory processes in epithelial cells, as well as in immune cells. Experiments in this report indicate that BCL10 is required for activation of nuclear factor (NF)-κB by both canonical and noncanonical pathways, following stimulation by the sulfated polysaccharide carrageenan (CGN). In wild type and IκB-kinase (IKK)α−/− mouse embryonic fibroblasts, increases in phospho-IκBα, nuclear NF-κB p65 (RelA) and p50, and KC, the mouse analog of human interleukin-8, were markedly reduced by silencing BCL10 or by exposure to the free radical scavenger Tempol. In IKKβ−/− cells, BCL10 silencing, but not Tempol, reduced the CGN-induced increases in KC, phospho-NF-κB-inducing kinase (NIK), cytoplasmic NF-κB p100, and nuclear NF-κB p52 and RelB, suggesting a BCL10 requirement for activation of the noncanonical pathway. In NCM460 cells, derived from normal, human colonic epithelium, the CGN-induced increases in NF-κB family members, p65, p50, p52, and RelB, were inhibited by BCL10 silencing. Although enzyme-linked immunosorbent assay and confocal images demonstrated no change in total NIK following CGN, increases in phospho-NIK in the wild type, IKKβ−/− and IKKα−/− cells were inhibited by silencing BCL10. These findings indicate an upstream signaling role for BCL10, in addition to its effects on IKKγ, the regulatory component of the IKK signalosome, and a requirement for BCL10 in both canonical and noncanonical pathways of NF-κB activation. Also, the commonly used food additive carrageenan can be added to the short list of known activators of both pathways.

      Introduction

      The importance of activation of B-cell lymphoma/CLL 10 (BCL10)
      The abbreviations used are: BCL10
      B-cell lymphoma/CLL 10
      CGN
      carrageenan
      WT
      wild type
      ELISA
      enzyme-linked immunosorbent assay
      ROS
      reactive oxygen species
      FACE
      fast-activated cell-based
      siRNA
      small interfering RNA
      NIK
      NF-κB-inducing kinase
      IKK
      IκB kinase
      SCBT
      Santa Cruz Biotechnology, Inc.
      MEF
      mouse embryonic fibroblast.
      has been recognized previously in the mucosa-associated lymphoid tissue (MALT) lymphomas, in which translocations involving MALT1 lead to constitutive activation of BCL10 and NF-κB transcription (
      • Zhang Q.
      • Siebert R.
      • Yan M.
      • Hinzmann B.
      • Cui X.
      • Xue L.
      • Rakestraw K.M.
      • Naeve C.W.
      • Beckmann G.
      • Weisenburger D.D.
      • Sanger W.G.
      • Nowotny H.
      • Vesely M.
      • Callet-Bauchu E.
      • Salles G.
      • Dixit V.M.
      • Rosenthal A.
      • Schlegelberger B.
      • Morris S.W.
      ,
      • Willis T.G.
      • Jadayel D.M.
      • Du M.Q.
      • Peng H.
      • Perry A.R.
      • Abdul-Rauf M.
      • Price H.
      • Karran L.
      • Majekodunmi O.
      • Wlodarska I.
      • Pan L.
      • Crook T.
      • Hamoudi R.
      • Isaacson P.G.
      • Dyer J.F.
      ). Other reports have defined a critical role for BCL10 in the inflammatory cascade in epithelial cells, including activation by lysophosphatidic acid (
      • Klemm S.
      • Zimmermann S.
      • Peschel C.
      • Mak T.W.
      • Ruland J.
      ), G-protein-coupled receptor (
      • Wang D.
      • You Y.
      • Lin P.C.
      • Xue L.
      • Morris S.W.
      • Zeng H.
      • Wen R.
      • Lin X.
      ), and angiotensin II (
      • McAllister-Lucas L.M.
      • Ruland J.
      • Siu K.
      • Jin X.
      • Gu S.
      • Kim D.S.
      • Kuffa P.
      • Kohrt D.
      • Mak T.W.
      • Nuñez G.
      • Lucas P.C.
      ). In this report, we demonstrate that BCL10 was required for NF-κB activation by both canonical and noncanonical pathways, following stimulation by the sulfated polysaccharide carrageenan (CGN) in mouse embryonic fibroblasts and in human colonic epithelial cells. Previously, we reported that CGN significantly up-regulated transcription of BCL10 in NCM460 cells (
      • Borthakur A.
      • Bhattacharyya S.
      • Dudeja P.K.
      • Tobacman J.K.
      ,
      • Bhattacharyya S.
      • Borthakur A.
      • Dudeja P.K.
      • Tobacman J.K.
      ).
      The sulfated polysaccharide carrageenan has been widely used for decades to induce inflammation in animal and tissue culture models. In our previous work, CGN was shown to induce an inflammatory cascade in human colonic epithelial cells by two distinct mechanisms: an immune-mediated mechanism involving TLR4 (toll-like receptor 4), IRAK (IL-1β receptor activating kinase), BCL10, phospho-IκBα (inhibitor of κB), NF-κB (nuclear factor κB), and IL-8 (interleukin-8); and a reactive oxygen species (ROS)-mediated mechanism involving phospho-Hsp27, IκB kinase (IKK)-β, phospho-IκBα, BCL10, NF-κB, and IL-8 (
      • Borthakur A.
      • Bhattacharyya S.
      • Dudeja P.K.
      • Tobacman J.K.
      ,
      • Bhattacharyya S.
      • Borthakur A.
      • Dudeja P.K.
      • Tobacman J.K.
      ,
      • Bhattacharyya S.
      • Dudeja P.K.
      • Tobacman J.K.
      ,
      • Bhattacharyya S.
      • Gill R.
      • Chen M.L.
      • Zhang F.
      • Linhardt R.J.
      • Dudeja P.K.
      • Tobacman J.K.
      ). Carrageenan activation of these pathways was attributable to its distinctive chemical structure, including its resemblance to the naturally occurring glycosaminoglycans, its highly sulfated galactose residues, and its unusual α-Gal(1→3)Gal bond that is a known immune epitope (
      • Bhattacharyya S.
      • Liu H.
      • Zhang Z.
      • Jam M.
      • Dudeja P.K.
      • Michel G.
      • Linhardt R.J.
      • Tobacman J.K.
      ,
      • Galili U.
      ). Because CGN is a commonly used food additive in the Western diet, these pathways may induce inflammation and disease in the human colon and implicate a role for BCL10 in human disease, in addition to the MALT lymphomas.
      To further define the BCL10-mediated activation of NF-κB and the interactions between the ROS and TLR4-BCL10 pathways, the requirements for different components of the IKK signaling complex and the responses of different members of the NF-κB family were investigated. The IKK signaling complex, including the catalytic components IKKα and IKKβ and the regulatory component IKKγ, also known as NEMO (NF-κB essential modifying factor), integrates upstream signals and leads to the phosphorylation of IκBα. Subsequently, phospho-IκBα is ubiquitinated, and the localization signal for NF-κB nuclear translocation is exposed. These events represent critical signals in the progression of the inflammatory cascade from a series of membrane events to a cellular reaction with transcriptional responses. To clarify the role of BCL10 with different components of the IKK signalosome and the subsequent effects on members of the NF-κB family, experiments with mouse embryonic fibroblasts that lack either IKKα or IKKβ were performed, and the inter-relationships among BCL10, phospho-NIK, and NF-κB family members, including p65, p100, p50, p52, RelB, and c-Rel, were determined.

      DISCUSSION

      BCL10 emerges as an important mediator of both the canonical and noncanonical pathways of NF-κB activation stimulated by CGN in NCM460 cells and MEF (Fig. 7). BCL10 was increased by CGN in both IKKα−/− and IKKβ−/− MEF, and BCL10 silencing by siRNA reduced CGN-induced stimulation of p65, p50, p100, p52, and RelB in MEF and NCM460 cells. These effects implicate BCL10 in the inflammatory cascade beyond its interaction with IKKγ and emphasize that BCL10 has a key role as a mediator of the innate immune response in epithelial, as well as its more established role in immune cells (
      • Zhou H.
      • Wertz I.
      • O'Rourke K.
      • Ultsch M.
      • Seshagiri S.
      • Eby M.
      • Xiao W.
      • Dixit V.M.
      ,
      • Drew D.
      • Shimada E.
      • Huynh K.
      • Bergqvist S.
      • Talwar R.
      • Karin M.
      • Ghosh G.
      ).
      Figure thumbnail gr7
      FIGURE 7Schematic of overall pathways of IL-8 activation by CGN in NCM460 cells. Carrageenan activates two major pathways of IL-8 activation: the TLR4-BCL10 pathway and the ROS-Hsp27 mediated pathway. These converge at the level of the IKK signalosome, in which effects on IKKα, -β, and -γ are integrated. Subsequently, in the NCM460 cells, members of the NF-κB family are activated, including p65 (RelA), p50, p100, p52, and RelB. The activation of phospho-NIK was repressed by BCL10 silencing. IRAK, interleukin-1 receptor-associated kinase; ubc, ubiquitin c; p, phosphorylated.
      Unexpectedly, the studies presented in this report revealed that CGN stimulated both the noncanonical, as well as the canonical pathway of NF-κB activation and that BCL10 was required for these effects upstream of the IKK signalosome. CGN joins the small group of known mediators of both the noncanonical and canonical pathways that includes lymphotoxin and B-cell activating factor (
      • Yilmaz Z.B.
      • Weih D.S.
      • Sivakumar V.
      • Weih F.
      ,
      • Endo T.
      • Nishio M.
      • Enzler T.
      • Cottam H.B.
      • Fukuda T.
      • James D.F.
      • Karin M.
      • Kipps T.J.
      ).
      By induction of both the canonical and noncanonical pathways of NF-κB activation, BCL10 and CGN are positioned to influence a wide range of NF-κB transcriptional effects. The p52/RelB heterodimer appears to bind to a broader spectrum of κB sites than the p50/RelA heterodimer and may even bind to a modified consensus sequence (
      • Fusco A.J.
      • Huang D.B.
      • Miller D.
      • Wang V.Y.
      • Vu D.
      • Ghosh G.
      ,
      • Wharry C.E.
      • Haines K.M.
      • Carroll R.G.
      • May M.J.
      ,
      • Dejardin E.
      ). By activation of the noncanonical pathway, CGN and BCL10 may evoke responses similar to those of tumor necrosis factor-α, as well as those elicited by inflammatory mediators such as dextran sulfate sodium that act through ROS (
      • Bhattacharyya S.
      • Dudeja P.K.
      • Tobacman J.K.
      ).
      The complexity of the negative feedback on NF-κB, involving mediators such as IκBδ, as well as IκB-α, -β, and -ϵ, may include stimulus specific responses and different, but specified kinetic rate constants (
      • Shih V.F.
      • Kearns J.D.
      • Basak S.
      • Savinova O.V.
      • Ghosh G.
      • Hoffmann A.
      ,
      • Savinova O.V.
      • Hoffmann A.
      • Ghosh G.
      ,
      • Basak S.
      • Shih V.F.
      • Hoffmann A.
      ,
      • Smith C.
      • Andreakos E.
      • Crawley J.B.
      • Brennan F.M.
      • Feldmann M.
      • Foxwell B.M.
      ). Also, the protein content of RelB was reported to be significantly reduced when p105 and p100 were absent, suggesting that the noncanonical pathway may be affected by intricate protein-protein relationships that exist among NF-κB components, as well as by transcriptional events. The interaction of these regulatory mechanisms with BCL10 poses an additional series of mechanistic interactions that require further investigation.
      The study findings demonstrated an increase in phospho-NIK following stimulation by CGN and showed localization of phospho-NIK to the outer cell membrane. BCL10 silencing inhibited the CGN-induced effects on phospho-NIK. These data challenge some previous observations about NIK activation, because previously, the LPS-activated TLR-mediated pathway was not associated with NIK (
      • Fusco A.J.
      • Savinova O.V.
      • Talwar R.
      • Kearns J.D.
      • Hoffmann A.
      • Ghosh G.
      ), and we have found that the TLR4-BCL10 mediated pathway resembles the CGN-activated pathway (
      • Bhattacharyya S.
      • Borthakur A.
      • Pant N.
      • Dudeja P.K.
      • Tobacman J.K.
      ). The data demonstrated that BCL10 silencing inhibited the increase in phospho-NIK, consistent with a vital role for BCL10 in the IKKα-mediated pathway, although the role of phospho-NIK in the IKKβ-mediated pathway remains obscure.
      The translocation of phospho-NIK to the outer cell membrane was unexpected but resembles changes shown upon activation of other molecules, including the catalytic subunit of (Na+ + K+)-ATPase and sphingosine kinase (SphK1) (
      • Myers A.C.
      • Bochner B.S.
      • Tomaselli G.F.
      • Fedarko N.
      • Hudson S.A.
      • Rohde H.
      • Huang S.K.
      • Xu K.Y.
      ,
      • ter Braak M.
      • Danneberg K.
      • Lichte K.
      • Liphardt K.
      • Ktistakis N.T.
      • Pitson S.M.
      • Hla T.
      • Jakobs K.H.
      • Zu Heringdorf D.M.
      ). SphK1 translocation to the plasma membrane from the cytosol involved activation of G(q)-coupled receptors, stimulation by platelet-derived growth factor, nerve growth factor, insulin-like growth factor, tumor necrosis factor-α, IgE, lysophosphatidic acid, or methacholine, and phosphorylation of Ser225. The phenomenon of “signaling inside out” has been associated with the SphK1 translocation, leading to the secretion of sphingosine-1-phosphate with subsequent cross-activation of sphingosine-1-phosphate G-protein-coupled receptors. No evidence exists at this time for involvement of G-protein-coupled receptor signaling or altered signaling dynamic of pNIK, although the SphK1 paradigm is provocative in consideration of how a localized stimulus can propagate. Altered cellular localization of pNIK following activation of NIK was observed previously in renal tubular cells from tissue preparations in models of ischemia-reperfusion (
      • Loverre A.
      • Ditonno P.
      • Crovace A.
      • Gesualdo L.
      • Ranieri E.
      • Pontrelli P.
      • Stallone G.
      • Infante B.
      • Schena A.
      • Di Paolo S.
      • Capobianco C.
      • Ursi M.
      • Palazzo S.
      • Battatglia M.
      • Selvaggi F.P.
      • Schena F.P.
      • Grandaliano G.
      ). The distinct localization along the outer surface of the cells is attributable to the large size of the carrageenan molecule, limiting its direct effect to cells on the surface, as noted previously with the CGN-TLR4 interaction (
      • Bhattacharyya S.
      • Gill R.
      • Chen M.L.
      • Zhang F.
      • Linhardt R.J.
      • Dudeja P.K.
      • Tobacman J.K.
      ).
      Vital questions remain regarding BCL10 interactions with other known mediators of inflammatory mechanisms in both immune and nonimmune cells. The CBM complex, comprised of Carma1 (CARD 11) or Carma3 (CARD 10), BCL10, and MALT1, has been identified as critical to propagation of the inflammatory stimulation, yet the precise mechanism of the CARD-CARD interaction between CARMA and BCL10 and the relationship to MALT1 and other mediators require further elucidation of the precise protein-protein interactions involved. In addition, other important mediators of the inflammatory cascade(s), including TRAFs 2, 3, 4, and 6, TAB1 and 2, as well as RIP, are intimately involved in the cellular inflammatory response, yet their activating or regulating functions with regard to BCL10 require further investigation. Interestingly, BCL10 silencing does not inhibit the effects of tumor necrosis factor-α (
      • Bhattacharyya S.
      • Pant N.
      • Dudeja P.K.
      • Tobacman J.K.
      ), implying that there may be multiple upstream mechanisms by which NIK is activated prior to interaction with IKKα. This combination of specificity and redundancy is consistent with a somewhat limited repertoire of cellular inflammatory responses to a more unlimited variety of extracellular stimuli that are integrated at the level of the IKK signalosome.
      Recent findings in our lab indicate that the BCL10 promoter contains a sequence that has a very high score (>90%) for likelihood as an NF-κB binding site (
      • Borthakur A.
      • Bhattacharyya S.
      • Alrefai W.
      • Tobacman J.
      • Ramaswamy K.
      • Dudeja P.K.
      ). This suggests the possibility that CGN may induce the constitutive activation of a BCL10/NF-κB loop, in which increases in BCL10 lead to increases in NF-κB and increases in NF-κB lead to increases in BCL10. This may lead to an ongoing cycle of inflammation, perhaps autonomous once initiated. Previously, in the MALT lymphomas, constitutive activation of NF-κB arose following chromosomal translocations that affected BCL10 (
      • Zhang Q.
      • Siebert R.
      • Yan M.
      • Hinzmann B.
      • Cui X.
      • Xue L.
      • Rakestraw K.M.
      • Naeve C.W.
      • Beckmann G.
      • Weisenburger D.D.
      • Sanger W.G.
      • Nowotny H.
      • Vesely M.
      • Callet-Bauchu E.
      • Salles G.
      • Dixit V.M.
      • Rosenthal A.
      • Schlegelberger B.
      • Morris S.W.
      ,
      • Willis T.G.
      • Jadayel D.M.
      • Du M.Q.
      • Peng H.
      • Perry A.R.
      • Abdul-Rauf M.
      • Price H.
      • Karran L.
      • Majekodunmi O.
      • Wlodarska I.
      • Pan L.
      • Crook T.
      • Hamoudi R.
      • Isaacson P.G.
      • Dyer J.F.
      ). In the setting of exogenous stimulation by CGN, it is possible that constitutive activation of NF-κB and BCL10 follows stimulation due to specific characteristics of the CGN related to its chemical structure, rather than to effects of a specific activating translocation.
      Recent publications demonstrate intense interest in the CBM complex in epithelial and endothelial, as well as immune cells (
      • Evans S.E.
      • Scott B.L.
      • Clement C.G.
      • Larson D.T.
      • Kontoyiannis D.
      • Lewis R.E.
      • Lasala P.R.
      • Pawlik J.
      • Peterson J.W.
      • Chopra A.K.
      • Klimpel G.
      • Bowden G.
      • Hook M.
      • Xu Y.
      • Tuvim M.J.
      • Dickey B.F.
      ,
      • Chang H.H.
      • Kuo M.Y.
      • Cheng S.J.
      • Chiang C.P.
      ,
      • Martin D.
      • Galisteo R.
      • Gutkind J.S.
      ,
      • Wu C.J.
      • Ashwell J.D.
      ,
      • Briones J.
      • Moga E.
      • Espinosa I.
      • Vergara C.
      • Alvarez E.
      • Villa J.
      • Bordes R.
      • Delgado J.
      • Prat J.
      • Sierra J.
      ), and increased attention to BCL10 and other CARD proteins may lead to enhanced understanding of these important inflammatory mechanisms. Also, because CGN has been so widely incorporated into a variety of foods in the Western diet, exposure to CGN may have a role in human disease, involving activation of inflammation through the BCL10-mediated pathways.

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