The brace helices of MLKL mediate interdomain communication and oligomerisation to regulate cell death by necroptosis

Davies, Katherine; Tanzer, Maria C.; Griffin, Michael D. W.; Mok, Yee Foong; Young, Samuel N.; Qin, Rui; Petrie, Emma J.; Czabotar, P.E.; Silke, John; Murphy, James M.

doi:10.1038/s41418-018-0061-3

Cited by 73 publications

(96 citation statements)

References 43 publications

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“…BAV Rmil and COTV157 were initially selected for our study because BAV and COTV could infect cultured human and mouse cells (Afonso et al, 2012). Nevertheless, the observation that necroptosis could be inhibited by their expression in both human and mouse cells was surprising considering the divergence in the necroptosis pathway mechanism (Davies et al, 2018;Petrie et al, 2018Petrie et al, , 2019Tanzer et al, 2016). To examine whether this was a general property of viral MLKL proteins, or whether host specificity has evolved, we examined the swinepox vMLKL ortholog SPV140, a protein with 34% amino acid identity to BAV Rmil and COTV157 ( Figure 1B).…”

Section: Vmlkl Proteins Block Necroptotic Signaling In Human and Mousmentioning

confidence: 99%

Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

et al. 2019

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Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinasedomain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit necroptosis by sequestering RIPK3 via its kinase domain to thwart MLKL engagement and phosphorylation. These data support an ancestral role for necroptosis in defense against pathogens. Furthermore, mimicry of a cellular pseudokinase by a pathogen adds to the growing repertoire of functions performed by pseudokinases in signal transduction.

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Section: Vmlkl Proteins Block Necroptotic Signaling In Human and Mousmentioning

confidence: 99%

Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

et al. 2019

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“…Necroptosis appears to be activated when recruitment of RIP1 by either TNFR1 or TRIF fails to result in caspase‐8 activation, thus sparing the cell from apoptosis. In the absence of apoptosis, RIP1 and RIP3 associate via their RHIM domains, forming an amyloid fibril; oligomerization and subsequent activation of RIP3 leads to the recruitment and phosphorylation of ‘mixed lineage kinase domain‐like protein (MLKL) via the N‐terminal kinase domain of RIP3, triggering MLKL oligomerization, recruitment to the plasma membrane and cell death, presumably by permeabilization of the membrane or disruption of membrane homeostasis …”

Section: Rhim Regionsmentioning

confidence: 99%

Death, TIR, and RHIM: Self-assembling domains involved in innate immunity and cell-death signaling

Nanson

Kobe

2018

Journal of Leukocyte Biology

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The innate immune system consists of pattern recognition receptors (PRRs) that detect pathogenand endogenous danger-associated molecular patterns (PAMPs and DAMPs), initiating signaling pathways that lead to the induction of cytokine expression, processing of pro-inflammatory cytokines, and induction of cell-death responses. An emerging concept in these pathways and associated processes is signaling by cooperative assembly formation (SCAF), which involves formation of higher order oligomeric complexes, and enables rapid and strongly amplified signaling responses to minute amounts of stimulus. Many of these signalosomes assemble through homotypic interactions of members of the death-fold (DF) superfamily, Toll/IL-1 receptor (TIR) domains, or the RIP homotypic interaction motifs (RHIM). We review the current understanding of the structure and function of these domains and their molecular interactions with a particular focus on higher order assemblies.

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“…During necroptosis, MLKL complexes with RIP1 and RIP3 in complex IIb, leading to phosphorylation of the pseudokinase domain (adjacent to the "brace" region recognized by our antibody [45]), which induces its oligomerization and translocation to the plasma membrane. The epitope recognized by our antibody may therefore have been blocked in complex IIb and more readily recognized after phosphorylation, oligomerization and plasma membrane translocation, meaning that we detected increased MLKL protein levels and its epitope earlier in the course of MLKL production and activity by Western blotting because of the open structure of the protein in this technique, but only later by immunohistochemistry after conformational and binding changes.…”

Section: Discussionmentioning

confidence: 99%

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Thomas

Thompson

Ahmed

2019

Cells

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Closed-globe injury can cause visual loss in military and civilian populations, with retinal cell death, including retinal ganglion cell (RGC) degeneration, leading to irreversible blindness. RGC and optic nerve (ON) degeneration after eye or head injury is termed traumatic optic neuropathy (TON). There are currently no treatments for RGC loss, therefore novel therapeutics to prevent RGC death or promote axonal regeneration are a priority. We investigated necroptotic signaling mechanisms in a rat blunt ocular injury model. After bilateral blunt trauma, protein expression and retinal localization of necroptosis pathway members (receptor interacting protein kinase 1, RIPK1; receptor interacting protein kinase 3, RIPK3; and mixed lineage kinase domain like pseudokinase, MLKL) were assessed by Western blot and immunohistochemistry (IHC), and potent necroptosis inhibitor Necrostatin-1s (Nec-1s) was delivered by intravitreal injection to one eye and vehicle to the contralateral eye. RGC and photoreceptor survival were assessed by cell counting and outer nuclear layer (ONL) thickness measurements on histology. The neuroprotective effects of Nec-1s were assessed in primary retinal culture by βIII-tubulin+ RGC cell counts. MLKL protein expression were upregulated at 48 h after injury and MLKL immunolocalised to retinal binding protein with multiple splice (RBPMS)+ RGC, inner nuclear cells and ONL cells, specifically at the retinal injury site. RIPK3 expression did not increase but RIPK3 co-immunolocalised with RBPMS+ RGC in intact and injured retinae. In vitro, a Nec-1s concentration of 0.01 pg/µL was RGC neuroprotective. In the blunt ocular injury rat model, Nec-1s prevented RGC death at the center of the impact site but did not protect against ONL thinning or provide functional restitution. RGC degeneration in our blunt ocular injury model is site-specific, with necroptosis driving death at the center of the focal impact site.

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The brace helices of MLKL mediate interdomain communication and oligomerisation to regulate cell death by necroptosis

Cited by 73 publications

References 43 publications

Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

Death, TIR, and RHIM: Self-assembling domains involved in innate immunity and cell-death signaling

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

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