Essential role of TAK1 in thymocyte development and activation

Abstract

The protein kinase TAK1 mediates the activation of NF-B in response to stimulation by proinflammatory cytokines and microbial pathogens in the innate immunity pathways. However, the physiological function of TAK1 in the adaptive immunity pathways is unclear. By engineering mice lacking TAK1 in T cells, here, we show that TAK1 is essential for thymocyte development and activation in vivo. Deletion of TAK1 prevented the maturation of single-positive thymocytes displaying CD4 or CD8, leading to reduction of T cells in the peripheral tissues. Thymocytes lacking TAK1 failed to activate NF-B and JNK and were prone to apoptosis upon stimulation. Our results provide the genetic evidence that TAK1 is required for the activation of NF-B in thymocytes and suggest that TAK1 plays a central role in both innate and adaptive immunity.T he Rel͞NF-B family of transcription factors regulates the expression of a plethora of genes involved in inflammation, immunity, and apoptosis (1, 2). NF-B is normally sequestered in the cytoplasm of unstimulated cells through its association with the I B family of inhibitory proteins. Stimulation of cells with a variety of agents leads to the rapid phosphorylation and subsequent degradation of I B by the ubiquitin-proteasome pathway, thus allowing NF-B to enter the nucleus to turn on various target genes.Phosphorylation of I B is catalyzed by a large kinase complex consisting of I B kinase (IKK)␣, IKK␤, and NEMO (also known as IKK␥ or IKKAP). The IKK complex integrates signals from diverse pathways, including those emanating from the receptors for TNF␣ and IL-1␤, Toll-like receptors (TLRs), and T cell receptors (TCRs) (3-6). Stimulation of IL-1R and some TLRs leads to the recruitment of several proteins, including the adaptor MyD88, the kinases IRAK4 and IRAK1, and the ubiquitin ligase TRAF6. TRAF6 functions in conjunction with the ubiquitin-conjugating enzyme (E2) complex Ubc13-Uev1A to catalyze the synthesis of Lys-63-linked polyubiquitin chains on certain protein targets, including TRAF6 itself (7,8). Polyubiquitinated TRAF6 activates a protein kinase complex consisting of the TAK1 kinase and the adaptor proteins TAB1 and TAB2 (8, 9). The activation of TAK1 by TRAF6 requires the binding between the K63 polyubiquitin chains and a conserved novel zinc finger (NZF) domain of TAB2 or its homologue TAB3 (10). After TAK1 is activated, it phosphorylates IKK␤ within the activation loop, resulting in the activation of IKK. TAK1 also phosphorylates and activates MKK6 and MKK7, leading to the activation of p38 and JNK kinase pathways.Recent studies have shown that TRAF-mediated polyubiquitination and the TAK1 kinase complex also play an important role in NF-B activation in T cells (11). Stimulation of TCR by an antigenic peptide and its cognate MHC activates a tyrosine kinase phosphorylation cascade, which, in turn, leads to the activation of protein kinase (PK)C . PKC then triggers the recruitment of the CARD domain proteins CARMA1 and BCL10 and the paracaspase MALT1 to lipid rafts (12)(13)(14). MALT1 ...

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

“…Several TCR signal regulators such as Themis and TAK1 have definitive roles during T cell development (38,39). Mice with these genes deleted in T cells displayed similar phenotypes to Ubc9-deficient mice reported in this article.…”

TAK1 control of cell death

“…4 Since this original finding, TAK1 also has been shown to be activated by a number of signaling molecules including cytokines such as TNFa and IL-1; ligands that interact with Toll-like receptors, B-cell receptor and T-cell receptor; and the lipotoxic molecule, ceramide. [5][6][7][8][9][10][11][12][13] Other endogenous death ligands of the TNF family, including TRAIL, also induce TAK1 activation. 14,15 Exogenous stressors and environmental changes such as osmotic stress, UV irradiation, ischemia and nutrient withdrawal activate TAK1.…”

“…57,83 Hematopoietic-specific Tak1 deletion depletes hematopoietic progenitor cells, T cells and macrophages. [10][11][12]58,[84][85][86][87] Deletion of TNF receptor 1 (Tnfr1) largely rescues these injuries and animal mortalities, 37,55,57,[82][83][84][85] demonstrating that TNFa is the major killer of Tak1-deficient cells in these tissues. However, some Tak1-deficient tissue injuries are still observed in Tnfr1-null background.…”

MAP3Ks as central regulators of cell fate during development

“…Interferon-inducible Cre-recombinase mediated deletion of TAK1 in adult mice results in bone marrow and liver failure due to increased apoptosis of hematopoietic cells and hepatocytes (Tang et al, 2008). Additionally, cells lacking TAK1 fail to activate the NF B and JNK cascades suggesting that TAK1 does promote cell survival by regulating apoptosis by means of these pathways (Liu et al, 2006;Tang et al, 2008). Conventional disruption of the TAK1 gene in mice causes a lethal phenotype by day E11.5 due to severe vascular defects and substantial delayed growth.…”