Editors' ChoiceImmunology

A transcription factor Sox it to bacterial DNA

Sci. Signal.  31 Mar 2015:
Vol. 8, Issue 370, pp. ec74
DOI: 10.1126/scisignal.aab2138

Neutrophils are immune cells that are the first responders at sites of infection, where they secrete antimicrobial factors, as well as cytokines and chemokines that recruit other immune cell types. Neutrophils contain membrane-bound Toll-like receptors (TLRs) with which to detect pathogens, but whether they have cytosolic sensors of microbial nucleic acids is unclear. Xia et al. found by flow cytometry and immunofluorescence staining that the transcription factor Sox2 was present in mouse neutrophils but not in other immune cell types. Subcellular fractionation assays showed that the transcription factor was predominantly cytosolic. When infected with the bacteria Listeria monocytogenes, mice with Sox2-deficient neutrophils exhibited increased mortality and bacterial burden compared with mice with normal neutrophils, and the mice with Sox2-deficient neutrophils had decreased amounts of proinflammatory cytokines in their serum. L. monocytogenes DNA is detected by cytosolic proteins that function as nucleic acid sensors in myeloid immune cells; however, genetic deletion of known DNA sensors in neutrophils did not block their production of proinflammatory cytokines in response to this pathogen. Bioinformatics analysis revealed the presence of Sox2-binding sequences in L. monocytogenes DNA, and double-stranded DNA matching these sequences (“matched” DNA) immunoprecipitated Sox2 from neutrophil lysates. Yeast two-hybrid analysis identified the adaptor protein TAB2 as a binding partner of Sox2, and immunofluorescence analysis showed that Sox2 associated with TAB2 and the kinase TAK1 in neutrophils transfected with matched, but not unmatched, L. monocytogenes DNA. Activation of the TAB2-TAK1 complex, which stimulates inflammatory NF-κB signaling, required the dimerization of Sox2. Knockdown of TAB2 or TAK1 in neutrophils blocked the expression of genes encoding inflammatory cytokines in response to L. monocytogenes DNA. Compared with control mice, mice with neutrophils that were deficient in either TAB2 or TAK1 were more susceptible to death in response to infection with L. monocytogenes. Together, these data suggest that the transcription factor Sox2 acts as a sequence-specific detector of bacterial DNA in neutrophils to stimulate the production of proinflammatory cytokines as part of the innate immune response (see commentary by Mankan and Hornung).

P. Xia, S. Wang, B. Ye, Y. Du, G. Huang, P. Zhu, Z. Fan, Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection. Nat. Immunol. 16, 366–375 (2015). [PubMed]

A. K. Mankan, V. Hornung, Sox2 as a servant of two masters. Nat. Immunol. 16, 335–336 (2015). [PubMed]

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