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RIPK1 Prevents Aberrant ZBP1-initiated Necroptosis

T. Berghe, W. Kaiser
Published 2017 · Medicine

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Receptor interacting protein kinase 1 (RIPK1) regulates inflammation and cell death, in host defense and homeostasis. The adaptor function of RIPK1 allows pro-survival and inflammatory signaling, while its kinase activity regulates the induction of necroptosis and apoptosis. A new level of regulation through its RIP homotypic interaction motif (RHIM) was recently discovered to suppress necroptosis and inflammation driven by the putative nucleic acid sensor protein Z-DNA binding protein 1 (ZBP1), also known as DAI. In the two decades following the discovery of RIPK1, RIPK1 has emerged as a master regulator of inflammatory signaling and cell death [1]. To date, important advances in our understanding of RIPK1 function continue to be uncovered. RIPK1-deficient mice fail to thrive, die within 1-3 days following birth and display extensive apoptosis. These observations prompted initial research efforts to focus on the role of RIPK1 in controlling pro-survival and inflammatory gene expression. More recently, RIPK1 kinase activity emerged as essential for coordinating death receptorinduced necrosis (Figure 1A). This type of necrosis was dubbed necroptosis upon the discovery of a chemical kinase inhibitor of RIPK1, necrostatin-1 (Nec1). However, the model of RIPK1 kinase functioning exclusively for necroptosis proved too simplistic as kinase activity was also found to be crucial for caspase 8-mediated apoptosis under conditions where cellular inhibitors of apoptosis (cIAPs) are depleted (Figure 1A). Thus, depending on the cellular content, RIPK1 kinase can initiate either necroptosis or apoptosis. This implies that a protective phenotype observed in response to Nec1 or in the context of RIPK1 kinase dead knockin mice (Ripk1KD mice) stems from the role of RIPK1 in regulating cell death but does not differentiate the cell death modality. Conditional deletion of RIPK1 in mice revealed additional complexity on the regulatory action of RIPK1. While absence of RIPK1 unleashes apoptosis in the intestinal epithelial cells [2, 3], necroptotic cell death dominates in the skin upon RIPK1 depletion [3]. RIPK1 kinase dead knock-in mice did not show any spontaneous phenotype indicating the sensitization to apoptosis in the gut upon RIPK1 deletion Editorial: Autophagy and Cell Death
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