Roberts JoAnn Simone, Yilmaz Ӧzlem
Department of Oral Biology, University of Florida, Gainesville, FL 32610, USA.
Department of Periodontology, University of Florida, P.O. Box 100434, Gainesville, FL 32610, USA.
Int J Mol Sci. 2015 Sep 28;16(10):23337-54. doi: 10.3390/ijms161023337.
Recently, the focus of murine caspase-11 and human orthologs caspase-4, -5 research has been on their novel function to induce noncanonical inflammasome activation in direct response to Gram-negative bacterial infection. On the other hand, a new role in anti-bacterial autophagy has been attributed to caspase-11, -4 and -5, which currently stands largely unexplored. In this review, we connect lately emerged evidence that suggests these caspases have a key role in anti-bacterial autophagy and discuss the growing implications of a danger molecule--extracellular ATP--and NADPH oxidase-mediated ROS generation as novel inducers of human caspase-4, -5 signaling during infection. We also highlight the adeptness of persistent pathogens like Porphyromonas gingivalis, a Gram-negative anaerobe and successful colonizer of oral mucosa, to potentially interfere with the activated caspase-4 pathway and autophagy. While, the ability of caspase-4, -5 to promote autophagolysosomal fusion is not well understood, the abundance of caspase-4 in skin and other mucosal epithelial cells implies an important role for caspase-4 in mucosal defense, supporting the view that caspase-4, -5 may play a non-redundant part in innate immunity. Thus, this review will join the currently disconnected cutting-edge research thereby proposing a working model for regulation of caspase-4, -5 in pathogen elimination via cellular-trafficking.
最近，小鼠半胱天冬酶-11及其人类同源物半胱天冬酶-4、-5的研究重点在于它们在直接响应革兰氏阴性菌感染时诱导非经典炎性小体激活的新功能。另一方面，半胱天冬酶-11、-4和-5在抗菌自噬中被赋予了新的作用，目前这方面的研究很大程度上尚未开展。在本综述中，我们将最近出现的证据联系起来，这些证据表明这些半胱天冬酶在抗菌自噬中起关键作用，并讨论了一种危险分子——细胞外ATP——以及NADPH氧化酶介导的活性氧生成作为感染期间人类半胱天冬酶-4、-5信号传导新诱导剂的日益重要的意义。我们还强调了像牙龈卟啉单胞菌这样的持续性病原体的适应性，牙龈卟啉单胞菌是一种革兰氏阴性厌氧菌，也是口腔黏膜的成功定植菌，它可能会干扰激活的半胱天冬酶-4途径和自噬。虽然半胱天冬酶-4、-5促进自噬溶酶体融合的能力尚未完全了解，但半胱天冬酶-4在皮肤和其他黏膜上皮细胞中的丰富表达意味着它在黏膜防御中起重要作用，支持了半胱天冬酶-4、-5可能在先天免疫中发挥非冗余作用的观点。因此，本综述将结合目前尚未关联的前沿研究，从而提出一个通过细胞运输调节半胱天冬酶-4、-5以消除病原体的工作模型。
