TRAF6 controls T cell homeostasis by maintaining the equilibrium of MALT1 scaffolding and protease functions.

MALT1 is a core component of the CARD11-BCL10-MALT1 (CBM) signalosome, in which it acts as a scaffold and a protease to bridge T cell receptor (TCR) ligation to immune activation. As a scaffold, MALT1 binds to TRAF6, and T cell-specific TRAF6 ablation or destruction of MALT1-TRAF6 interaction provokes activation of conventional T (Tconv) effector cells. In contrast, MALT1 protease activity controls the development and suppressive function of regulatory T (Treg) cells in a T cell-intrinsic manner.

Optimized CRISPR-Cas9-based Strategy for Complex Gene Targeting in Murine Embryonic Stem Cells for Germline Transmission.

Although CRISPR-Cas9 genome editing can be performed directly in single-cell mouse zygotes, the targeting efficiency for more complex modifications such as the insertion of two loxP sites, multiple mutations in cis, or the precise insertion or deletion of longer DNA sequences often remains low (Cohen, 2016). Thus, targeting and validation of correct genomic modification in murine embryonic stem cells (ESCs) with subsequent injection into early-stage mouse embryos may still be preferable, allowing for large-scale screening before transfer of thoroughly characterized and genetically defined ESC clones into the germline. This procedure can result in a reduction of animal numbers with cost effectiveness and compliance with the 3R principle of animal welfare regulations.

Prdm6 controls heart development by regulating neural crest cell differentiation and migration.

The molecular mechanisms that drive the acquisition of distinct neural crest cell (NCC) fates is still poorly understood. Here, we identified Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating cardiac NCCs (CNCCs). Using transcriptomic analysis and genetic and fate mapping approaches in transgenic mice, we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction.

TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease.

Balanced control of T cell signaling is critical for adaptive immunity and protection from autoimmunity. By combining genetically engineered mouse models, biochemical analyses and pharmacological interventions, we describe an unexpected dual role of the tumor necrosis factor receptor–associated factor 6 (TRAF6) E3 ligase as both a positive and negative regulator of mucosa-associated lymphoid tissue 1 (MALT1) paracaspase. Although MALT1-TRAF6 recruitment is indispensable for nuclear factor κB signaling in activated T cells, TRAF6 counteracts basal MALT1 protease activity in resting T cells.