Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii.

Published

Journal Article

Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the zeta isoform of the DGK family (DGKzeta) is expressed in macrophages (Mphi) and dendritic cells. DGKzeta deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor alpha production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKzeta negatively controls the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and that inhibition of PI3K activity or treatment with PA can restore lipopolysaccharide-induced IL-12 production by DGKzeta-deficient Mphi. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKzeta promotes TLR responses via a pathway involving inhibition of PI3K.

Full Text

Duke Authors

Cited Authors

  • Liu, C-H; Machado, FS; Guo, R; Nichols, KE; Burks, AW; Aliberti, JC; Zhong, X-P

Published Date

  • April 16, 2007

Published In

Volume / Issue

  • 204 / 4

Start / End Page

  • 781 - 792

PubMed ID

  • 17371930

Pubmed Central ID

  • 17371930

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.20061856

Language

  • eng

Conference Location

  • United States