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TBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases. | LitMetric

AI Article Synopsis

  • The cytokine TNF can lead to a type of cell death influenced by RIPK1, but this can be suppressed by two proteins, TANK and AZI2, which help regulate TBK1 kinase activation.
  • Mice lacking both TANK and AZI2 experience severe health issues like multi-organ inflammation and early death, which can be mitigated by disabling TNFR1 or using a modified RIPK1.
  • TANK and AZI2 work together in the TNF receptor signaling process, binding to different components at distinct times to maintain TBK1 activity and protect against excessive inflammation.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576971PMC
http://dx.doi.org/10.1038/s41467-024-54399-4DOI Listing

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