1 Ocak 2021 Dergi makalesi Açık Erişim

Taft, Justin; Markson, Michael; Legarda, Diana; Patel, Roosheel; Chan, Mark; Malle, Louise; Richardson, Ashley; Gruber, Conor; Martin-Fernandez, Marta; Mancini, Grazia M. S.; van Laar, Jan A. M.; van Pelt, Philomine; Buta, Sofija; Wokke, Beatrijs H. A.; Sabli, Ira K. D.; Sancho-Shimizu, Vanessa; Chavan, Pallavi Pimpale; Schnappauf, Oskar; Khubchandani, Raju; Cuceoglu, Muserref Kasap; Cuceoglu, Muserref Kasap

Citation Style Language JSON

{
  "DOI": "10.1016/j.cell.2021.07.026", 
  "abstract": "TANK binding kinase 1 (TBK1) regulates IFN-I, NF-kappa B, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-kappa B. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.", 
  "author": [
    {
      "family": "Taft", 
      "given": " Justin"
    }, 
    {
      "family": "Markson", 
      "given": " Michael"
    }, 
    {
      "family": "Legarda", 
      "given": " Diana"
    }, 
    {
      "family": "Patel", 
      "given": " Roosheel"
    }, 
    {
      "family": "Chan", 
      "given": " Mark"
    }, 
    {
      "family": "Malle", 
      "given": " Louise"
    }, 
    {
      "family": "Richardson", 
      "given": " Ashley"
    }, 
    {
      "family": "Gruber", 
      "given": " Conor"
    }, 
    {
      "family": "Martin-Fernandez", 
      "given": " Marta"
    }, 
    {
      "family": "Mancini", 
      "given": " Grazia M. S."
    }, 
    {
      "family": "van Laar", 
      "given": " Jan A. M."
    }, 
    {
      "family": "van Pelt", 
      "given": " Philomine"
    }, 
    {
      "family": "Buta", 
      "given": " Sofija"
    }, 
    {
      "family": "Wokke", 
      "given": " Beatrijs H. A."
    }, 
    {
      "family": "Sabli", 
      "given": " Ira K. D."
    }, 
    {
      "family": "Sancho-Shimizu", 
      "given": " Vanessa"
    }, 
    {
      "family": "Chavan", 
      "given": " Pallavi Pimpale"
    }, 
    {
      "family": "Schnappauf", 
      "given": " Oskar"
    }, 
    {
      "family": "Khubchandani", 
      "given": " Raju"
    }, 
    {
      "family": "Cuceoglu", 
      "given": " Muserref Kasap"
    }, 
    {
      "family": "Cuceoglu", 
      "given": " Muserref Kasap"
    }
  ], 
  "container_title": "CELL", 
  "id": "230168", 
  "issue": "17", 
  "issued": {
    "date-parts": [
      [
        2021, 
        1, 
        1
      ]
    ]
  }, 
  "page": "4447-+", 
  "title": "Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death", 
  "type": "article-journal", 
  "volume": "184"
}