Nature2014-06-24 3:47 PM

死亡细胞的处理机制被澄清 Unexpected link between an antibiotic, pannexin channels and apoptosis

论文摘要 

凋亡细胞的胞质膜上的Pannexin 1通道介导 “find-me” 分子信号的释放,这种信号吸引吞噬细胞,后者的任务是清除死亡的细胞。在对小分子所做的一项无偏筛选中,Kodi Ravichandran及同事发现喹诺酮抗体Trovafloxacin是Pannexin 1通道活性的一种直接抑制分子,导致凋亡细胞的失控碎片化。这项工作确定了Pannexin通道在凋亡细胞的有序分解中扮演一个必要角色,同时还可能重新激发人们对与Pannexin 1通道没有交叉反应的喹诺酮抗体的兴趣,这种交叉反应也许可解释在Trovafloxacin的临床试验中所出现的特别毒性。

Abstract 

Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. Here we show that the quinolone antibiotic trovafloxacin is a novel PANX1 inhibitor, by using a small-molecule screen. Although quinolones are widely used to treat bacterial infections, some quinolones have unexplained side effects, including deaths among children. PANX1 is a direct target of trovafloxacin at drug concentrations seen in human plasma, and its inhibition led to dysregulated fragmentation of apoptotic cells. Genetic loss of PANX1 phenocopied trovafloxacin effects, revealing a non-redundant role for pannexin channels in regulating cellular disassembly during apoptosis. Increase in drug-resistant bacteria worldwide and the dearth of new antibiotics is a major human health challenge. Comparing different quinolone antibiotics suggests that certain structural features may contribute to PANX1 blockade. These data identify a novel linkage between an antibiotic, pannexin channels and cellular integrity, and suggest that re-engineering certain quinolones might help develop newer antibacterials.

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