The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapter NEMO, AZI2 is recruited later via deubiquitinase A20. In summary, our data show that TANK and AZI2 cooperatively sustain TBK1 activity during different stages of TNF receptor assembly to protect against autoinflammation.

• MeSH
• Adaptor Proteins, Signal Transducing * metabolism   genetics   MeSH
• Cell Death MeSH
• Endopeptidases MeSH
• Intracellular Signaling Peptides and Proteins metabolism   genetics   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout * MeSH
• Mice MeSH
• Protein Serine-Threonine Kinases * metabolism   genetics   MeSH
• Receptors, Tumor Necrosis Factor, Type I * metabolism   genetics   MeSH
• Receptor-Interacting Protein Serine-Threonine Kinases * metabolism   genetics   MeSH
• Signal Transduction MeSH
• Tumor Necrosis Factor-alpha * metabolism   MeSH
• Tumor Necrosis Factor alpha-Induced Protein 3 metabolism   genetics   MeSH
• Inflammation metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by the T-cell antigen receptors (TCR) and co-stimulatory or inhibitory receptors. The molecular regulation of these complex signaling networks is still incompletely understood. Here, we identify the adaptor protein ABIN1 as a component of the signaling complexes of GITR and OX40 co-stimulation receptors. T cells lacking ABIN1 are hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, and superior ability to induce experimental autoimmune diabetes in mice. ABIN1 negatively regulates p38 kinase activation and late NF-κB target genes. P38 is at least partially responsible for the upregulation of the key effector proteins IFNG and GZMB in ABIN1-deficient T cells after TCR stimulation. Our findings reveal the intricate role of ABIN1 in T-cell regulation.

• MeSH
• Adaptor Proteins, Signal Transducing * metabolism   genetics   MeSH
• Lymphocyte Activation immunology   genetics   MeSH
• T-Lymphocytes, Cytotoxic * immunology   metabolism   MeSH
• Diabetes Mellitus, Type 1 immunology   genetics   metabolism   MeSH
• Glucocorticoid-Induced TNFR-Related Protein MeSH
• Interferon-gamma metabolism   MeSH
• Humans MeSH
• p38 Mitogen-Activated Protein Kinases metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• NF-kappa B metabolism   MeSH
• Receptors, Antigen, T-Cell metabolism   MeSH
• Receptors, OX40 metabolism   genetics   MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

IL-17 mediates immune protection from fungi and bacteria, as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of linear ubiquitin chain assembly complex (LUBAC) as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   metabolism   MeSH
• HEK293 Cells MeSH
• HeLa Cells MeSH
• I-kappa B Kinase genetics   metabolism   MeSH
• Humans MeSH
• Protein Serine-Threonine Kinases genetics   metabolism   MeSH
• Receptors, Interleukin-17 genetics   metabolism   MeSH
• Signal Transduction * MeSH
• Feedback, Physiological * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH