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Abstract
Inflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival. One example of this balance is the tightly regulated transition from TNFR1-associated pro-inflammatory complex I to pro-death complex II. By contrast, here we show that a TRIF-dependent complex containing FADD, RIPK1 and caspase-8 (that we have termed the TRIFosome) mediates cell death in response to Yersinia pseudotuberculosis and LPS. Furthermore, we show that constitutive binding between ZBP1 and RIPK1 is essential for the initiation of TRIFosome interactions, caspase-8-mediated cell death and inflammasome activation, thus positioning ZBP1 as an effector of cell death in the context of bacterial blockade of pro-inflammatory signaling. Additionally, our findings offer an alternative to the TNFR1-dependent model of complex II assembly, by demonstrating pro-death complex formation reliant on TRIF signaling.
Highlights
Inflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival
As we have shown previously[11], LPS/5z7 induced a mixed cell death phenotype, that was partially dependent on the kinase activity of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), the apoptotic caspases CASP3 and CASP7, and the effector of pyroptosis gasdermin D (GSDMD), and entirely dependent on CASP8 (Fig. 1a)
We identified the TLR4 adaptor TIR-domain-containing adapter-inducing interferon-β (TRIF) as an important mediator of CASP8-driven cell death, as death in Trif−/− bone marrow-derived macrophages (BMDMs) treated with LPS/5z7 was abrogated to levels similar to those induced by 5z7 alone, which induces a mechanistically divergent, TNF-dependent form of necrotic cell death that is dependent on CASP8 as described previously[11] (Fig. 1b)
Summary
Inflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival. We show that constitutive binding between ZBP1 and RIPK1 is essential for the initiation of TRIFosome interactions, caspase-8-mediated cell death and inflammasome activation, positioning ZBP1 as an effector of cell death in the context of bacterial blockade of pro-inflammatory signaling. Yersinia species bacteria release effector proteins known as Yersinia outer proteins (Yops), which are capable of modulating these host responses in favor of bacterial survival and replication[2] One such effector, YopJ blocks activation of the level 3 MAP kinase TAK1 (TGFβ-activated kinase), attenuating host inflammatory and pro-survival signaling[3,4]. We and others have identified a form of pyroptosislike cell death that occurs in murine macrophages in response to Yersinia infection[11,12] This YopJ-dependent death relied on the kinase activity of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to drive caspase-8 (CASP8) activation, and the cleavage of downstream caspases-1, 3, 7, 9, and 1111,12. To reflect the mandatory requirement for TRIF rather than for TNFR1 for these pro-death interactions involving ZBP1, we have named this complex the TRIFosome
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