细胞坏死和细胞凋亡是两类不同方式的死亡模式。坏死是一种细胞破裂性死亡，细胞内物质会释放到细胞周围引起炎症。而凋亡则属于一种默默的萎缩性死亡方式，细胞最终被巨噬细胞吞噬，不会引起明显的炎症反应。自从10年前发现细胞坏死具有程序性以后，这个领域成为基础生物医学的研究热点，众多著名学者涉猎这一领域。这是因为，程序性意味着可控制性，通过研究有希望进行克服，这为解决炎症性疾病带来新的希望。2005年哈佛大学华人学者发现了具有阻断这一过程的特定小分子化合物给这一领域的研究提供了重要工具。过去许多人研究发现，如果对两种死亡方式中的一种进行压制，可以导致另一种死亡方式的加强。但关于坏死和凋亡之间的相互关系和调控方式仍不十分了解。最近牛顿等学者在《科学》发表一篇论文，对理解坏死和凋亡之间的关系带来了曙光。他们通过对两个和细胞死亡关系十分密切的两个基因（RIPK1和RIPK3）进行失活性突变，就是这种动物能表达这些基因，但表达的基因失去特定功能（但不是所有功能）。结果发现，和基因敲除的情况最显著的区别是，如果把RIPK3基因蛋白突变，动物虽然不容易发生细胞坏死，但更容易发生依赖于Caspase8的细胞凋亡，而且更容易死亡。通过深入研究发现，RIPK3是细胞坏死的核心，更重要的是细胞内决定细胞死亡方式的分子转换器。

Receptor-interacting protein kinase 1 (RIPK1) and RIPK3trigger pro-inflammatory cell death termed “necroptosis.” Studies withRIPK3-deficient mice or the RIPK1 inhibitor necrostatin-1 suggest thatnecroptosis exacerbates pathology in many disease models. We engineered miceexpressing catalytically inactive RIPK3 D161N or RIPK1 D138N to determine theneed for the active kinase in the whole animal. Unexpectedly, RIPK3 D161Npromoted lethal RIPK1- and caspase-8–dependent apoptosis. In contrast, miceexpressing RIPK1 D138N were viable and, like RIPK3-deficient mice, resistant totumor necrosis factor (TNF)–induced hypothermia. Cells expressing RIPK1 D138Nwere resistant to TNF-induced necroptosis, whereas TNF-induced signalingpathways promoting gene transcription were unperturbed. Our data indicate thatthe kinase activity of RIPK3 is essential for necroptosis but also governswhether a cell activates caspase-8 and dies by apoptosis.

Trying to protect animals from one form of cell deathmay lead to death by another. Two protein kinases, known as RIPK1 and RIPK3promote signaling that leads to cell death by necroptosis. However, Newton etal. (p. 1357, published online 20 February; see the Perspective by Zhang andChan) found that inhibition of RIPK3 was not always beneficial. Instead, miceexpressing a form of RIPK3 with no catalytic activity died from increasedapoptotic cell death, but animals lacking the RIPK3 protein entirely, did notdie perhaps because RIPK3 restrains apoptosis mediated by caspase-8 by anindependent mechanism.