Essential function for the kinase TAK1 in innate and adaptive immune responses

Abstract

Transforming growth factor-beta-activated kinase 1 (TAK1) has been linked to interleukin 1 receptor and tumor necrosis factor receptor signaling. Here we generated mouse strains with conditional expression of a Map3k7 allele encoding part of TAK1. TAK1-deficient embryonic fibroblasts demonstrated loss of responses to interleukin 1beta and tumor necrosis factor. Studies of mice with B cell-specific TAK1 deficiency showed that TAK1 was indispensable for cellular responses to Toll-like receptor ligands, CD40 and B cell receptor crosslinking. In addition, antigen-induced immune responses were considerably impaired in mice with B cell-specific TAK1 deficiency. TAK1-deficient cells failed to activate transcription factor NF-kappaB and mitogen-activated protein kinases in response to interleukin 1beta, tumor necrosis factor and Toll-like receptor ligands. However, TAK1-deficient B cells were able to activate NF-kappaB but not the kinase Jnk in response to B cell receptor stimulation. These results collectively indicate that TAK1 is key in the cellular response to a variety of stimuli.

TLR signaling

“…Embryonic fibroblasts and B cells derived from TAK1-deficient mice show reduced NF-kB, JNK and p38 activation in response to various TLR ligands. 37 Furthermore, ERK1 and ERK2 activation was also reduced in TAK1-deficient B cells. 37 Thus, TAK1 is required for the activation of NF-kB and MAP kinase family members in TLR signaling ( Figure 2).…”

“…37 Furthermore, ERK1 and ERK2 activation was also reduced in TAK1-deficient B cells. 37 Thus, TAK1 is required for the activation of NF-kB and MAP kinase family members in TLR signaling ( Figure 2). Other members of MAP3K, MEKK3 and Tpl2 (also known as Cot1) are also implicated in the activation of MAP kinase activation in TLR4 signaling.…”

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.…”

“…Lethal E10-11 8,25,119 (Epidermis) Increased cell death-4Lethal P5-7 82 (Intestinal epithelium) Increased cell death-4Lethal P0 55 (Inducible intestinal epithelium) Ileitis and loss of paneth cells 55,65 (Endothelium/blood vessel) Increased cell death, defective vascularization-4Lethal E10-11 37 (Liver) Increased cell death-4Hepatocellular carcinoma within 6 weeks of age 57,83 (Hematopoietic system) Increased cell death-4Depletion of stem cells [84][85][86] (Myeloid) Macrophage death, splenomegaly and hyperproliferation of neutrophils 87,89 Tab1 Lethal E15-16 120 There is a well-studied inhibitory regulation from apoptosis to necroptosis (Figure 4, blue inhibition arrow). Thus, inhibition of caspase-8 activates necroptosis.…”

An N‐Ethyl‐N‐Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion

“…However this Map3k7 variant did not cosegregate with the HVF phenotype, and involvement of this missense Map3k7 variant in causing HVF is unlikely, and consistent with other observations from mutant mouse and human disease studies. Thus, homozygous Map3k7 knockout mice are embryonically lethal, and heterozygous Map3k7 knockout mice have no phenotype 59, 60. Moreover, osteoblast‐specific Map3k7 knockout mice developed clavicular hypoplasia and delayed closure of the fontanelles, similar to the human disorder of cleidocranial dysplasia, reduced trabecular bone, and a moderate decrease in body weight, but did not develop vertebral defects 61.…”