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 >> 细胞生物学 提交时间: 2016-05-11
摘要: Angiogenesis, a process that newly-formed blood vessels sprout from pre-existing ones, is vital for vertebrate development and adult homeostasis. Previous studies have demonstrated that the neuronal guidance molecule netrin-1 participates in angiogenesis and morphogenesis of the vascular system. Netrin-1 exhibits dual activities in angiogenesis: either promoting or inhibiting angiogenesis. The anti-angiogenic activity of netrin-1 is mediated by UNC5B receptor. However, how netrin-1 promotes angiogenesis remained unclear. Here we report that CD146, an endothelial transmembrane protein of the immunoglobulin superfamily, is a receptor for netrin-1. Netrin-1 binds to CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner. Conditional knockout of the cd146 gene in the murine endothelium or disruption of netrin-CD146 interaction by a specific anti-CD146 antibody blocks or reduces netrin-1-induced angiogenesis. In zebrafish embryos, downregulating either netrin-1a or CD146 results in vascular defects with striking similarity. Moreover, knocking down CD146 blocks ectopic vascular sprouting induced by netrin-1 overexpression. Together, our data uncover CD146 as a previously unknown receptor for netrin-1 and also reveal a functional ligand for CD146 in angiogenesis, demonstrating the involvement of netrin-CD146 signaling in angiogenesis during vertebrate development.