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MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling

Lynn Elton (UGent) , Isabelle Carpentier (UGent) , Jens Staal (UGent) , Yasmine Driege (UGent) , Mira Haegman (UGent) and Rudi Beyaert (UGent)
(2016) FEBS JOURNAL. 283(3). p.403-412
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
Human paracaspase 1 (PCASP1), better known as mucosa associated lymphoid tissue lymphoma translocation 1 (MALT1), plays a key role in immunity and inflammation by regulating gene expression in lymphocytes and other immune cell types. Deregulated MALT1 activity has been implicated in autoimmunity, immunodeficiency and certain types of lymphoma. As a scaffold MALT1 assembles downstream signaling proteins for nuclear factor-B (NF-B) activation, while its proteolytic activity further enhances NF-B activation by cleaving NF-B inhibitory proteins. MALT1 also processes and inactivates a number of mRNA destabilizing proteins, whichfurther fine-tunes gene expression. MALT1 protease inhibitors are currently developed for therapeutic targeting. Here we show that T cell activation, as well as overexpression of the oncogenic fusion protein API2-MALT1, induces the MALT1-mediated cleavage of haem-oxidized IRP2 ubiquitin ligase 1 (HOIL-1). In addition, to acting as a K48-polyubiquitin specific E3 ubiquitin ligase for different substrates, HOIL-1 co-operates in a catalytic-independent manner with the E3 ubiquitin ligase HOIL-1L interacting protein (HOIP) as part of the linear ubiquitin chain assembly complex (LUBAC). Intriguingly, cleavage of HOIL-1 does not directly abolish its ability to support HOIP-induced NF-B signaling, which is still mediated by the N-terminal cleavage fragment, but generates a C-terminal fragment with LUBAC inhibitory properties. We propose that MALT1-mediated HOIL-1 cleavage provides a gain-of-function mechanism that is involved in the negative feedback regulation of NF-B signaling.
Keywords
INFLAMMATION, ABC-DLBCL, PROTECTS MICE, nuclear factor-kappa B, MALT1, lymphocytes, ubiquitin, LUBAC, PARACASPASE MALT1, COMBINED IMMUNODEFICIENCY, LYMPHOID-TISSUE, PHARMACOLOGICAL INHIBITION, LINEAR UBIQUITINATION, GENE-EXPRESSION, INDEPENDENT ROLE

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Citation

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Chicago
Elton, Lynn, Isabelle Carpentier, Jens Staal, Yasmine Driege, Mira Haegman, and Rudi Beyaert. 2016. “MALT1 Cleaves the E3 Ubiquitin Ligase HOIL-1 in Activated T Cells, Generating a Dominant Negative Inhibitor of LUBAC-induced NF-κB Signaling.” Febs Journal 283 (3): 403–412.
APA
Elton, L., Carpentier, I., Staal, J., Driege, Y., Haegman, M., & Beyaert, R. (2016). MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling. FEBS JOURNAL, 283(3), 403–412.
Vancouver
1.
Elton L, Carpentier I, Staal J, Driege Y, Haegman M, Beyaert R. MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling. FEBS JOURNAL. 2016;283(3):403–12.
MLA
Elton, Lynn, Isabelle Carpentier, Jens Staal, et al. “MALT1 Cleaves the E3 Ubiquitin Ligase HOIL-1 in Activated T Cells, Generating a Dominant Negative Inhibitor of LUBAC-induced NF-κB Signaling.” FEBS JOURNAL 283.3 (2016): 403–412. Print.
@article{7141600,
  abstract     = {Human paracaspase 1 (PCASP1), better known as mucosa associated lymphoid tissue lymphoma translocation 1 (MALT1), plays a key role in immunity and inflammation by regulating gene expression in lymphocytes and other immune cell types. Deregulated MALT1 activity has been implicated in autoimmunity, immunodeficiency and certain types of lymphoma. As a scaffold MALT1 assembles downstream signaling proteins for nuclear factor-B (NF-B) activation, while its proteolytic activity further enhances NF-B activation by cleaving NF-B inhibitory proteins. MALT1 also processes and inactivates a number of mRNA destabilizing proteins, whichfurther fine-tunes gene expression. MALT1 protease inhibitors are currently developed for therapeutic targeting. Here we show that T cell activation, as well as overexpression of the oncogenic fusion protein API2-MALT1, induces the MALT1-mediated cleavage of haem-oxidized IRP2 ubiquitin ligase 1 (HOIL-1). In addition, to acting as a K48-polyubiquitin specific E3 ubiquitin ligase for different substrates, HOIL-1 co-operates in a catalytic-independent manner with the E3 ubiquitin ligase HOIL-1L interacting protein (HOIP) as part of the linear ubiquitin chain assembly complex (LUBAC). Intriguingly, cleavage of HOIL-1 does not directly abolish its ability to support HOIP-induced NF-B signaling, which is still mediated by the N-terminal cleavage fragment, but generates a C-terminal fragment with LUBAC inhibitory properties. We propose that MALT1-mediated HOIL-1 cleavage provides a gain-of-function mechanism that is involved in the negative feedback regulation of NF-B signaling.},
  author       = {Elton, Lynn and Carpentier, Isabelle and Staal, Jens and Driege, Yasmine and Haegman, Mira and Beyaert, Rudi},
  issn         = {1742-464X},
  journal      = {FEBS JOURNAL},
  language     = {eng},
  number       = {3},
  pages        = {403--412},
  title        = {MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-\ensuremath{\kappa}B signaling},
  url          = {http://dx.doi.org/10.1111/febs.13597},
  volume       = {283},
  year         = {2016},
}

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