Centre for Research in Therapeutic Solutions, Health Research Institute, University of Canberra, Canberra, ACT, Australia.
Sci Rep. 2018 Jan 25;8(1):1569. doi: 10.1038/s41598-018-19839-4.
Human Rhinovirus (HRV) is a pathogen of significant medical importance, being a major cause of upper respiratory tract infections (common colds) as well as causing the majority of virus-induced asthma exacerbations. We investigated whether HRV could modulate apoptosis, an innate antiviral response. Apoptotic signals are generated either extrinsically or intrinsically and are propagated via caspase cascades that lead to cell death, reducing viral replication, which relies on cellular machinery. Using HRV16 infected cells, in combination with chemical inducers and inhibitors of extrinsic apoptosis we show that HRV16 3C protease cleaves a key intermediate in extrinsic apoptosis. Receptor-interacting protein kinase-1 (RIPK1), an extrinsic apoptosis adaptor protein, was cleaved by caspase 8, as expected, during chemical induction of apoptosis. RIPK1 was cleaved in HRV infection albeit at a different site. Caspase 8 activation, which is associated with extrinsic apoptosis, was concurrent with HRV 3C protease mediated cleavage of RIPK1, and potentially increased the accessibility of the HRV 3C cleavage site within RIPK1 in-vitro. The caspase 8 mediated RIPK1 cleavage product has a pro-apoptotic function, and further cleavage of this pro-apoptotic cleavage product by HRV 3C may provide a mechanism by which HRV limits apoptosis.
人鼻病毒（HRV）是一种具有重要医学意义的病原体，是上呼吸道感染（普通感冒）的主要原因，也是导致大多数病毒引起的哮喘加重的原因。我们研究了 HRV 是否可以调节细胞凋亡，这是一种先天的抗病毒反应。凋亡信号可以通过外源性或内源性途径产生，并通过半胱天冬酶级联反应传播，导致细胞死亡，从而减少依赖于细胞机制的病毒复制。我们使用 HRV16 感染的细胞，结合外源性凋亡的化学诱导剂和抑制剂，表明 HRV16 3C 蛋白酶切割外源性凋亡的关键中间产物。受体相互作用蛋白激酶-1（RIPK1）是外源性凋亡衔接蛋白，在化学诱导凋亡过程中，如预期的那样，被半胱天冬酶 8 切割。在 HRV 感染中，RIPK1 被切割，尽管切割位点不同。与外源性凋亡相关的半胱天冬酶 8 的激活与 HRV 3C 介导的 RIPK1 切割同时发生，并且可能增加了 HRV 3C 在体外切割 RIPK1 内部切割位点的可及性。半胱天冬酶 8 介导的 RIPK1 切割产物具有促凋亡功能，HRV 3C 进一步切割这种促凋亡切割产物可能为 HRV 限制细胞凋亡提供了一种机制。
