分类: 生物学 >> 生物物理学 >> 免疫学 提交时间: 2016-05-12
摘要: NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-kappa B pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-kappa B essential modulator ubiquitination to trigger the Ubc13-mediated NF-kappa B pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.
分类: 生物学 >> 生物物理学 >> 免疫学 提交时间: 2016-05-12
摘要: Neutrophils express Toll-like receptors (TLRs) for the recognition of conserved bacterial elements to initiate antimicrobial responses. However, whether other cytosolic DNA sensors are expressed by neutrophils remains elusive. Here we found constitutive expression of the transcription factor Sox2 in the cytoplasm of mouse and human neutrophils. Neutrophil-specific Sox2 deficiency exacerbated bacterial infection. Sox2 directly recognized microbial DNA through its high-mobility-group (HMG) domain. Upon challenge with bacterial DNA, Sox2 dimerization was needed to activate a complex of the kinase TAK1 and its binding partner TAB2, which led to activation of the transcription factors NE-kappa B and AP-1 in neutrophils. Deficiency in TAK1 or TAB2 impaired Sox2-mediated antibacterial immunity. Overall, we reveal a previously unrecognized role for Sox2 as a cytosolic sequence-specific DNA sensor in neutrophils, which might provide potential therapeutic strategies for the treatment of infectious diseases.