TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease

O’Neill, Thomas; Seeholzer, Thomas; Gewies, Andreas; Gehring, Torben; Giesert, Florian; Hamp, Isabel; Graß, Carina; Kriegsmann, Katharina; Tofaute, Marie J.; Demski, Katrin; Poth, Tanja; Rosenbaum, Marc; Schnalzger, Theresa; Ruland, Jürgen; Göttlicher, Martin; Kriegsmann, Mark; Naumann, Ronald; Heissmeyer, Vigo; Plettenburg, Oliver; Wurst, Wolfgang; Krappmann, Daniel

doi:10.1126/sciimmunol.abh2095

Cited by 18 publications

(34 citation statements)

References 59 publications

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“…A recent report has now uncovered a previously unrecognized constitutive MALT1 protease activity, which is dampened through MALT1 interactions with TRAF6 through a so-far elusive mechanism. In this study the absence of TRAF6 or mutations in MALT1 impairing the interaction with TRAF6, enhanced the T cell activation independent protease activity of MALT1 and caused flagrant autoimmunity in mice (61). Reflecting constitutive MALT1 activity, Roquin-1 and Roquin-2 exhibit more constitutive cleavage by MALT1 than Regnase-1 in naive mature T cells (30).…”

Section: Perspectivesmentioning

confidence: 67%

Cooperation of RNA-Binding Proteins – a Focus on Roquin Function in T Cells

Behrens

Heissmeyer

2022

Front. Immunol.

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Post-transcriptional gene regulation by RNA-binding proteins (RBPs) is important in the prevention of inflammatory and autoimmune diseases. With respect to T cell activation and differentiation, the RBPs Roquin-1/2 and Regnase-1 play pivotal roles by inducing degradation and/or translational silencing of target mRNAs. These targets encode important proinflammatory mediators and thus Roquin and Regnase-1 functions dampen cellular programs that can lead to inflammation and autoimmune disease. Recent findings demonstrate direct physical interaction of both RBPs. Here, we propose that cooperativity of trans-acting factors may be more generally used to reinforce the regulatory impact on selected targets and promote specific cell fate decisions. We develop this concept for Roquin and Regnase-1 function in resting and activated T cells and discuss the involvement in autoimmunity as well as how the therapeutic potential can be used in anti-tumor therapies.

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Section: Perspectivesmentioning

confidence: 67%

Cooperation of RNA-Binding Proteins – a Focus on Roquin Function in T Cells

Behrens

Heissmeyer

2022

Front. Immunol.

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“…Loss of protein expression was analyzed by Western blotting and genomic alterations were analyzed by sequencing of genomic DNA. CARD11, BCL10, MALT1, HOIP and TRAF6 KO cells have previously been described [ 6 , 34 – 37 ]. For experiments with human CD4 T cells, peripheral blood mononuclear cells (PBMC) from healthy donors were freshly isolated by density gradient sedimentation using Ficoll-Paque Plus (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

“…Positive regulators recruited to the active CBM core complex include the E3 ligases TRAF6 and LUBAC, consisting of HOIP, HOIL-1 and SHARPIN. By catalyzing the ubiquitination of BCL10 and MALT1, these E3 ligases trigger IKK/NF-κB activation [ 3 – 6 ]. In contrast, the deubiquitinating enzymes (DUBs) CYLD and A20 (TNFAIP3) act as negative regulators of TCR signaling that limit NF-κB activation in an adaptive immune response [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-κB signaling in activated T cells

Yin

Karayel

Chao

et al. 2022

Cell. Mol. Life Sci.

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T cell activation initiates protective adaptive immunity, but counterbalancing mechanisms are critical to prevent overshooting responses and to maintain immune homeostasis. The CARD11-BCL10-MALT1 (CBM) complex bridges T cell receptor engagement to NF-κB signaling and MALT1 protease activation. Here, we show that ABIN-1 is modulating the suppressive function of A20 in T cells. Using quantitative mass spectrometry, we identified ABIN-1 as an interactor of the CBM signalosome in activated T cells. A20 and ABIN-1 counteract inducible activation of human primary CD4 and Jurkat T cells. While A20 overexpression is able to silence CBM complex-triggered NF-κB and MALT1 protease activation independent of ABIN-1, the negative regulatory function of ABIN-1 depends on A20. The suppressive function of A20 in T cells relies on ubiquitin binding through the C-terminal zinc finger (ZnF)4/7 motifs, but does not involve the deubiquitinating activity of the OTU domain. Our mechanistic studies reveal that the A20/ABIN-1 module is recruited to the CBM complex via A20 ZnF4/7 and that proteasomal degradation of A20 and ABIN-1 releases the CBM complex from the negative impact of both regulators. Ubiquitin binding to A20 ZnF4/7 promotes destructive K48-polyubiquitination to itself and to ABIN-1. Further, after prolonged T cell stimulation, ABIN-1 antagonizes MALT1-catalyzed cleavage of re-synthesized A20 and thereby diminishes sustained CBM complex signaling. Taken together, interdependent post-translational mechanisms are tightly controlling expression and activity of the A20/ABIN-1 silencing module and the cooperative action of both negative regulators is critical to balance CBM complex signaling and T cell activation.

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“…The central caspase-like domain of MALT1 has been bioinformatically identified due to its homology to the protease domains of caspases and it is responsible for the protease activity of MALT1 [ 34 ]. Whereas in non-activated T cells, TRAF6 and GRK2 suppress the protease activity of MALT1, monoubiquitination and dimerization activate MALT1 protease function, leading to the cleavage of selected substrates [ 35 , 36 , 37 , 38 ]. In contrast to caspases, which cleave their substrates after the acidic amino acid aspartate, MALT1 cleaves proteins after the positively charged arginine [ 39 , 40 ].…”

Section: Malt1 Protease Functionmentioning

confidence: 99%

The Paracaspase MALT1 in Cancer

et al. 2022

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Almost twenty years ago, the importance of the paracaspase MALT1 in antigen receptor-induced NF-κB activation was first described. Since then, several other immune receptors, G-protein-coupled receptors, and receptor tyrosine kinases were identified as relying on MALT1 to induce NF-κB activation. In various hematological malignancies and solid tumors, MALT1 is constitutively activated and drives chronic NF-κB target gene expression. Deregulated MALT1 activity in cancer thus promotes tumor cell survival, proliferation, and metastasis. Since the molecular function of MALT1 partially requires its protease activity, pharmacological targeting of MALT1 may represent a promising anti-cancer strategy. Here, we review the molecular features of MALT1 activation and function as well as the therapeutic potential of MALT1 inhibition in hematological malignancies and solid tumors.

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TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease

Abstract: TRAF6 maintains immune homeostasis by preventing deregulated activation of the MALT1 paracaspase in T cells.

Cited by 18 publications

References 59 publications

Cooperation of RNA-Binding Proteins – a Focus on Roquin Function in T Cells

Cooperation of RNA-Binding Proteins – a Focus on Roquin Function in T Cells

A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-κB signaling in activated T cells

The Paracaspase MALT1 in Cancer

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