RGD Reference Report - The uric acid crystal receptor Clec12A potentiates type I interferon responses. - Rat Genome Database

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The uric acid crystal receptor Clec12A potentiates type I interferon responses.

Authors: Li, Kai  Neumann, Konstantin  Duhan, Vikas  Namineni, Sukumar  Hansen, Anne Louise  Wartewig, Tim  Kurgyis, Zsuzsanna  Holm, Christian K  Heikenwalder, Mathias  Lang, Karl S  Ruland, J├╝rgen 
Citation: Li K, etal., Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18544-18549. doi: 10.1073/pnas.1821351116. Epub 2019 Aug 26.
RGD ID: 41412202
Pubmed: (View Article at PubMed) PMID:31451663
DOI: Full-text: DOI:10.1073/pnas.1821351116

The detection of microbes and damaged host cells by the innate immune system is essential for host defense against infection and tissue homeostasis. However, how distinct positive and negative regulatory signals from immune receptors are integrated to tailor specific responses in complex scenarios remains largely undefined. Clec12A is a myeloid cell-expressed inhibitory C-type lectin receptor that can sense cell death under sterile conditions. Clec12A detects uric acid crystals and limits proinflammatory pathways by counteracting the cell-activating spleen tyrosine kinase (Syk). Here, we surprisingly find that Clec12A additionally amplifies type I IFN (IFN-I) responses in vivo and in vitro. Using retinoic acid-inducible gene I (RIG-I) signaling as a model, we demonstrate that monosodium urate (MSU) crystal sensing by Clec12A enhances cytosolic RNA-induced IFN-I production and the subsequent induction of IFN-I-stimulated genes. Mechanistically, Clec12A engages Src kinase to positively regulate the TBK1-IRF3 signaling module. Consistently, Clec12A-deficient mice exhibit reduced IFN-I responses upon lymphocytic choriomeningitis virus (LCMV) infection, which affects the outcomes of these animals in acute and chronic virus infection models. Thus, our results uncover a previously unrecognized connection between an MSU crystal-sensing receptor and the IFN-I response, and they illustrate how the sensing of extracellular damage-associated molecular patterns (DAMPs) can shape the immune response.


Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Clec12a  (C-type lectin domain family 12, member A)

Genes (Mus musculus)
Clec12a  (C-type lectin domain family 12, member a)

Genes (Homo sapiens)
CLEC12A  (C-type lectin domain family 12 member A)

Additional Information