RHIM-based protein:protein interactions in microbial defence against programmed cell death by necroptosis

Baker, Max O. D. G.; Shanmugam, Nirukshan; Pham, Chi L.L.; Strange, Merryn; Steain, Megan; Sunde, Margaret

doi:10.1016/j.semcdb.2018.05.004

Cited by 27 publications

(26 citation statements)

References 88 publications

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“…Previous study indicates that TRADD competes with RIPK1 to bind TNFR (Zheng et al, 2006), so it is possible to raise the hypothesis that TRADD and RIPK1 compete to bind RIPK3 to form functional protein complex in necroptosis induction. As RIPK1 binds RIPK3 through their shared RHIM domain, which is more optimal than other protein domain in mediating protein interaction, it is more capable for RIPK1 than TRADD to be recruited by RIPK3 to initiate necroptosis (Wu et al, 2014;Baker et al, 2018). Therefore, TRADD is dispensable for necroptosis induction in the presence of RIPK1, and knockdown of RIPK1 facilitates the interaction between TRADD and RIPK3, resulting in TRADDdependent necroptosis.…”

Section: Discussionmentioning

confidence: 99%

TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor

Wang¹,

Chang²,

Feng³

et al. 2020

Front. Cell Dev. Biol.

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As a programmed necrotic cell death, necroptosis has the intrinsic initiators, including receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which combine to form necroptotic signaling pathway and mediate necroptosis induced by various necroptotic stimuli, such as tumor necrosis factor (TNF). Although chemical inhibition of RIPK1 blocks TNFinduced necroptosis, genetic elimination of RIPK1 does not suppress but facilitate necroptosis triggered by TNF. Moreover, RIPK3 has been reported to mediate the RIPK1-independent necroptosis, but the involved mechanism is unclear. In this study, we found that TRADD was essential for TNF-induced necroptosis in RIPK1-knockdown L929 and HT-22 cells. Mechanistic study demonstrated that TRADD bound RIPK3 to form new protein complex, which then promoted RIPK3 phosphorylation via facilitating RIPK3 oligomerization, leading to RIPK3-MLKL signaling pathway activation. Therefore, TRADD acted as a partner of RIPK3 to initiate necroptosis in RIPK1-knockdown L929 and HT-22 cells in response to TNF stimulation. In addition, TRADD was critical for the accumulation of reactive oxygen species (ROS), which contributed to RIPK1independent necroptosis triggered by TNF. Collectively, our data demonstrate that TRADD acts as the new target protein for TNF-induced RIPK3 activation and the subsequent necroptosis in a RIPK1-independent manner.

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Section: Discussionmentioning

confidence: 99%

TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor

Wang¹,

Chang²,

Feng³

et al. 2020

Front. Cell Dev. Biol.

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“…Many of the currently recognized viral protein inhibitors of necroptosis contain a RHIM [37]. MCMV encodes a RHIM close to the N-terminus of a non-functional ribonucleotide reductase, M45.…”

Section: Plos Pathogensmentioning

confidence: 99%

Varicella zoster virus encodes a viral decoy RHIM to inhibit cell death

et al. 2020

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Herpesviruses are known to encode a number of inhibitors of host cell death, including RIP Homotypic Interaction Motif (RHIM)-containing proteins. Varicella zoster virus (VZV) is a member of the alphaherpesvirus subfamily and is responsible for causing chickenpox and shingles. We have identified a novel viral RHIM in the VZV capsid triplex protein, open reading frame (ORF) 20, that acts as a host cell death inhibitor. Like the human cellular RHIMs in RIPK1 and RIPK3 that stabilise the necrosome in TNF-induced necroptosis, and the viral RHIM in M45 from murine cytomegalovirus that inhibits cell death, the ORF20 RHIM is capable of forming fibrillar functional amyloid complexes. Notably, the ORF20 RHIM forms hybrid amyloid complexes with human ZBP1, a cytoplasmic sensor of viral nucleic acid. Although VZV can inhibit TNF-induced necroptosis, the ORF20 RHIM does not appear to be responsible for this inhibition. In contrast, the ZBP1 pathway is identified as important for VZV infection. Mutation of the ORF20 RHIM renders the virus incapable of efficient spread in ZBP1expressing HT-29 cells, an effect which can be reversed by the inhibition of caspases. Therefore we conclude that the VZV ORF20 RHIM is important for preventing ZBP1-driven apoptosis during VZV infection, and propose that it mediates this effect by sequestering ZBP1 into decoy amyloid assemblies.

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“…RHIM-containing necroptosis regulators have been found in viruses [20,21]. M45 from murine cytomegalovirus (MCMV) has been reported to inhibit the virus-induced DAI-RIP3 necroptosis pathway [22].…”

Section: Introductionmentioning

confidence: 99%

RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif

et al. 2020

Cell Death Differ

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Necroptosis is mediated by signaling complexes called necrosomes, which contain receptor-interacting protein 3 (RIP3) and upstream effectors, such as RIP1. In necrosomes, the RIP homotypic interaction motif (RHIM) of RIP3 and RIP1 forms amyloidal complex. But how the amyloidal necrosomes control RIP3 activation and cell necroptosis has not been determined. Here, we showed that RIP3 amyloid fibrils could further assemble into large fibrillar networks which presents as cellular puncta during necroptosis. A viral RHIM-containing necroptosis inhibitor M45 could form heteroamyloid with RIP3 in cells and prevent RIP3 puncta formation and cell necroptosis. We characterized mutual antagonism between RIP3-RHIM and M45-RHIM in necroptosis regulation, which was caused by distinct inter-filament interactions in RIP3, M45 amyloids revealed with atomic force microscopy. Moreover, double mutations Asn464 and Met468 in RIP3-RHIM to Asp disrupted RIP3 kinase-dependent necroptosis. While the mutant RIP3(N464D/M468D) could form amyloid as wild type upon necroptosis induction. Based on these results, we propose that RIP3 amyloid formation is required but not sufficient in necroptosis signaling, the ordered inter-filament assembly of RIP3 is critical in RIP3 amyloid mediated kinase activation and cell necroptosis.

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RHIM-based protein:protein interactions in microbial defence against programmed cell death by necroptosis

Cited by 27 publications

References 88 publications

TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor

TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor

Varicella zoster virus encodes a viral decoy RHIM to inhibit cell death

RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif

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