Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The API2–MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling

Oncogene volume 33, pages 2520–2530 (2014)Cite this article

Subjects

Abstract

The API2-MALT1 fusion oncoprotein is created by the recurrent t(11;18)(q21;q21) chromosomal translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. We identified receptor interacting protein-1 (RIP1) as a novel API2–MALT1-associated protein, and demonstrate that RIP1 is required for API2–MALT1 to stimulate canonical nuclear factor kappa B (NF-κB). API2–MALT1 promotes ubiquitination of RIP1 at lysine (K) 377, which is necessary for full NF-κB activation. Furthermore, we found that TNF receptor-associated factor 2 (TRAF2) recruitment is required for API2–MALT1 to induce RIP1 ubiquitination, NF-κB activation and cellular transformation. Although both TRAF2 and RIP1 interact with the API2 moiety of API2–MALT1, this moiety alone is insufficient to induce RIP1 ubiquitination or activate NF-κB, indicating that API2–MALT1-dependent RIP1 ubiquitination represents a gain of function requiring the concerted actions of both the API2 and MALT1 moieties of the fusion. Intriguingly, constitutive RIP1 ubiquitination was recently demonstrated in several solid tumors, and now our study implicates RIP1 ubiquitination as a critical component of API2–MALT1-dependent lymphomagenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Isaacson PG, Du MQ . MALT lymphoma: from morphology to molecules. Nat Rev Cancer 2004; 4: 644–653.

    Article  CAS  PubMed  Google Scholar 

  2. Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 1999; 93: 3601–3609.

    CAS  PubMed  Google Scholar 

  3. Akagi T, Motegi M, Tamura A, Suzuki R, Hosokawa Y, Suzuki H et al. A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 1999; 18: 5785–5794.

    Article  CAS  PubMed  Google Scholar 

  4. Morgan JA, Yin Y, Borowsky AD, Kuo F, Nourmand N, Koontz JI et al. Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res 1999; 59: 6205–6213.

    CAS  PubMed  Google Scholar 

  5. Liu H, Ye H, Ruskone-Fourmestraux A, De Jong D, Pileri S, Thiede C et al. T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication. Gastroenterology 2002; 122: 1286–1294.

    Article  CAS  PubMed  Google Scholar 

  6. Liu H, Ye H, Dogan A, Ranaldi R, Hamoudi RA, Bearzi I et al. T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood 2001; 98: 1182–1187.

    Article  CAS  PubMed  Google Scholar 

  7. Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 1999; 96: 35–45.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Q, Siebert R, Yan M, Hinzmann B, Cui X, Xue L et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 1999; 22: 63–68.

    Article  CAS  PubMed  Google Scholar 

  9. Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G et al. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood 2003; 101: 2335–2339.

    Article  CAS  PubMed  Google Scholar 

  10. Hoffmann A, Baltimore D . Circuitry of nuclear factor kappaB signaling. Immunol Rev 2006; 210: 171–186.

    Article  PubMed  Google Scholar 

  11. Uren AG, O'Rourke K, Aravind LA, Pisabarro MT, Seshagiri S, Koonin EV et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol Cell 2000; 6: 961–967.

    CAS  PubMed  Google Scholar 

  12. Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed ME, Chen FF et al. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem 2001; 276: 19012–19019.

    Article  CAS  PubMed  Google Scholar 

  13. Thome M, Charton JE, Pelzer C, Hailfinger S . Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol 2010; 2: a003004.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M et al. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 2004; 427: 167–171.

    Article  CAS  PubMed  Google Scholar 

  15. Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ . The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 2004; 14: 289–301.

    Article  CAS  PubMed  Google Scholar 

  16. Oeckinghaus A, Wegener E, Welteke V, Ferch U, Arslan SC, Ruland J et al. Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. EMBO J 2007; 26: 4634–4645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A et al. Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 2011; 331: 468–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhou H, Du MQ, Dixit VM . Constitutive NF-kappaB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity. Cancer Cell 2005; 7: 425–431.

    Article  CAS  PubMed  Google Scholar 

  19. Lucas PC, Kuffa P, Gu S, Kohrt D, Kim DS, Siu K et al. A dual role for the API2 moiety in API2-MALT1-dependent NF-kappaB activation: heterotypic oligomerization and TRAF2 recruitment. Oncogene 2007; 26: 5643–5654.

    Article  CAS  PubMed  Google Scholar 

  20. Garrison JB, Samuel T, Reed JC . TRAF2-binding BIR1 domain of c-IAP2/MALT1 fusion protein is essential for activation of NF-kappaB. Oncogene 2009; 28: 1584–1593.

    Article  CAS  PubMed  Google Scholar 

  21. Rothe M, Wong SC, Henzel WJ, Goeddel DV . A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 1994; 78: 681–692.

    Article  CAS  PubMed  Google Scholar 

  22. Hsu H, Shu HB, Pan MG, Goeddel DV . TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1996; 84: 299–308.

    Article  CAS  PubMed  Google Scholar 

  23. Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV . TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 1996; 4: 387–396.

    Article  CAS  PubMed  Google Scholar 

  24. Vince JE, Pantaki D, Feltham R, Mace PD, Cordier SM, Schmukle AC et al. TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (tnf) to efficiently activate nf-{kappa}b and to prevent tnf-induced apoptosis. J Biol Chem 2009; 284: 35906–35915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 2008; 30: 689–700.

    Article  CAS  PubMed  Google Scholar 

  26. Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K et al. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J Biol Chem 2008; 283: 24295–24299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 2010; 465: 1084–1088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ . Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 2006; 22: 245–257.

    Article  CAS  PubMed  Google Scholar 

  29. Li H, Kobayashi M, Blonska M, You Y, Lin X . Ubiquitination of RIP is required for tumor necrosis factor alpha-induced NF-kappaB activation. J Biol Chem 2006; 281: 13636–13643.

    Article  CAS  PubMed  Google Scholar 

  30. Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD . Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol 2006; 8: 398–406.

    Article  CAS  PubMed  Google Scholar 

  31. Conze DB, Zhao Y, Ashwell JD . Non-canonical NF-kappaB activation and abnormal B cell accumulation in mice expressing ubiquitin protein ligase-inactive c-IAP2. PLoS Biol 2010; 8: e1000518.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lee TH, Shank J, Cusson N, Kelliher MA . The kinase activity of Rip1 is not required for tumor necrosis factor-alpha-induced IkappaB kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2. J Biol Chem 2004; 279: 33185–33191.

    Article  CAS  PubMed  Google Scholar 

  33. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008; 4: 313–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. O'Donnell MA, Legarda-Addison D, Skountzos P, Yeh WC, Ting AT . Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol 2007; 17: 418–424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Baens M, Fevery S, Sagaert X, Noels H, Hagens S, Broeckx V et al. Selective expansion of marginal zone B cells in Emicro-API2-MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination. Cancer Res 2006; 66: 5270–5277.

    Article  CAS  PubMed  Google Scholar 

  36. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 2011; 471: 591–596.

    Article  CAS  PubMed  Google Scholar 

  37. Lu J, Bai L, Sun H, Nikolovska-Coleska Z, McEachern D, Qiu S et al. SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP. Cancer Res 2008; 68: 9384–9393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stoffel A, Chaurushiya M, Singh B, Levine AJ . Activation of NF-kappaB and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis. Proc Natl Acad Sci USA 2004; 101: 9079–9084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Noels H, van Loo G, Hagens S, Broeckx V, Beyaert R, Marynen P et al. A Novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-kappaB activation by API2middle dotMALT1 fusions. J Biol Chem 2007; 282: 10180–10189.

    Article  CAS  PubMed  Google Scholar 

  40. Duprez L, Bertrand MJ, Vanden Berghe T, Dondelinger Y, Festjens N, Vandenabeele P . Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis. J Biol Chem 2012; 287: 14863–14872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, Matsumoto K, Gaynor RB . TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J Mol Biol 2003; 326: 105–115.

    Article  CAS  PubMed  Google Scholar 

  42. Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A et al. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell 2004; 15: 535–548.

    Article  CAS  PubMed  Google Scholar 

  43. Bellail AC, Olson JJ, Yang X, Chen ZJ, Hao C . A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. Cancer Discov 2012; 2: 140–155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang Y, Xia F, Hermance N, Mabb A, Simonson S, Morrissey S et al. A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-kappaB and p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 responses to DNA damage. Mol Cell Biol 2011; 31: 2774–2786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yin Q, Lamothe B, Darnay BG, Wu H . Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry 2009; 48: 10558–10567.

    Article  CAS  PubMed  Google Scholar 

  46. Cardamone MD, Krones A, Tanasa B, Taylor H, Ricci L, Ohgi KA et al. A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2. Mol Cell 2012; 46: 91–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Peng C, Zhu F, Wen W, Yao K, Li S, Zykova T et al. TRAF2 is a key mediator of the EGF-induced RSK2/CREB/Fos signaling pathway. J Biol Chem 2012; 287: 25881–25892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shembade N, Ma A, Harhaj EW . Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes. Science 2010; 327: 1135–1139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol 2008; 9: 263–271.

    Article  CAS  PubMed  Google Scholar 

  50. Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P et al. T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J 2011; 30: 1742–1752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ting AT, Pimentel-Muinos FX, Seed B . RIP mediates tumor necrosis factor receptor 1 activation of NF-kappaB but not Fas/APO-1-initiated apoptosis. EMBO J 1996; 15: 6189–6196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nunez G et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J 2008; 27: 373–383.

    Article  CAS  PubMed  Google Scholar 

  53. Biton S, Ashkenazi A . NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling. Cell 2011; 145: 92–103.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Gabriel Nuñez for contributing plasmids, Shaomeng Wang for providing smac mimetic compounds and Linda Klei for laboratory management. This work was supported by the Shirley K Schlafer Foundation, the Elizabeth Caroline Crosby Fund, and grants from the University of Michigan Comprehensive Cancer Center (G007839) and the National Cancer Institute, NIH (R01CA124540). SR was supported by the National Heart, Lung and Blood Institute, NIH (T32-HL007622-21A2), the Nancy Newton Loeb Pediatric Cancer Research Award and the AACI Fellowship for Translational Cancer Research.

Author information

Author notes

  1. S Rosebeck

    Present address: 7Current address: Multiple Myeloma Program, University of Chicago, Chicago, IL 60637, USA.,

  2. D Kohrt

    Present address: 8Current address: Department of Biology, Connecticut College, New London, CT 06320, USA.,

  3. P C Lucas

    Present address: 9Current address: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,

  4. L M McAllister-Lucas

    Present address: 10Current address: Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.,

  5. P C Lucas and L M McAllister-Lucas: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA

    S Rosebeck, A O Rehman, D Kohrt & L M McAllister-Lucas

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    I J Apel & P C Lucas

  3. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Laboratory Block, Addenbrooke’s Hospital, Cambridge, UK

    A Appert & M-Q Du

  4. Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    M A O'Donnell & A T Ting

  5. Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, Catholic University Leuven, Leuven, Belgium

    M Baens

  6. Department of Molecular and Developmental Genetics, Human Genome Laboratory, Flanders Institute for Biotechnology (VIB), Leuven, Belgium

    M Baens

Authors
  1. S Rosebeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A O Rehman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I J Apel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Kohrt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Appert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M A O'Donnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A T Ting
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M-Q Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Baens
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P C Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L M McAllister-Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to P C Lucas or L M McAllister-Lucas.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rosebeck, S., Rehman, A., Apel, I. et al. The API2–MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling. Oncogene 33, 2520–2530 (2014). https://doi.org/10.1038/onc.2013.195

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.195

Keywords

This article is cited by

Search

Advanced search

Quick links