myeloid-innate-signaling-pathway-regulation-malt1-paracaspase

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Besides its function in lymphoid cells, which has been addressed by numerous studies, the paracaspase MALT1 also plays an important role in innate cells ...

Novartis Institutes for BioMedical Research

Selective MALT1 paracaspase inhibition does not block TNF-α production downstream of TLR4 in myeloid cells.

A CARD10-Dependent Tonic Signalosome Activates MALT1 Paracaspase and Regulates IL-17/TNF-α-Driven Keratinocyte Inflammation.

The MALT1 (Mucosa associated lymphoid tissue lymphoma translocation protein 1) paracaspase couples antigen receptors on lymphocytes to downstream signaling events. Activation of MALT1 is known to involve stimulus-dependent CBM complex formation, that is, the recruitment of BCL10-bound MALT1 to a CARD-Coiled Coil protein. Beyond this canonical, CBM-dependent mechanism of MALT1 activation, recent studies suggest that MALT1 protease activity may be triggered by alternative mechanisms. For instance, the E3-ligase TRAF6 can activate MALT1 proteolytic function and induce MALT1 auto-cleavage. However, the interplay between CBM and TRAF6 with regard to MALT1 activation has remained incompletely elucidated. Here, by generating CRISPR/Cas9-derived knock-out Jurkat T-cells, we show that TRAF6 was dispensable for CARD11/BCL10-dependent MALT1 activation upon T-cell stimulation. However, ectopically-expressed TRAF6 could induce MALT1 activity in Jurkat T-cells devoid of either CARD11 or BCL10. These data provide unequivocal evidence that TRAF6-mediated MALT1 activation does not require the upstream scaffold CARD11 or the interaction between MALT1 and BCL10. Thus, TRAF6 may be part of a previously unidentified non-canonical pathway that triggers MALT1 protease activity independently of canonical CBM signalosomes.

Frederic Bornancin

Autoimmunity,
Transplantation and Inflammation,
Autoimmunity, Transplantation and Inflammation

Novartis Institutes for BioMedical Research

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Frederic Bornancin

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Novartis Institutes for BioMedical Research

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Autoimmunity,
Transplantation and Inflammation,
Autoimmunity, Transplantation and Inflammation