ArticleMolecular biology and evolution2021
Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation.
Article in Molecular biology and evolution, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 40 citations in OpenAlex.
- The factory enters the fray: how mitochondrial protein trafficking shapes the host response to infection.Journal of virology · 2026Review
- Z-Nucleic Acid-Binding Protein (ZBP)1 (DAI/DLM1) Regulation in Antiviral Cell Death Pathways.Pathogens (Basel, Switzerland) · 2026Review
- Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.IUBMB life · 2026Review
- The evolutionary dynamics between viral mimics and host proteins.Molecular systems biology · 2026Article
- Apoptosis as an evolutionary battleground: pathogen pressure and the shaping of programmed cell death pathways.Frontiers in cell and developmental biology · 2026Review
- Mammalian innate antiviral defenses: beyond interferon.Journal of virology · 2025Review
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Pirfenidone Mitigates Transforming Growth Factor-β-induced Inflammation after Viral Infection.American journal of respiratory cell and molecular biology · 2025Article
- Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates.eLife · 2025Article
- Viral piracy of host RNA phosphatase DUSP11 by avipoxviruses.PLoS pathogens · 2025Article
- Review
- An Evolutionary Framework Exploiting Virologs and Their Host Origins to Inform Poxvirus Protein Functions.Methods in molecular biology (Clifton, N.J.) · 2025Article
- For Better or Worse: The Impact of Necrotic Cell Death Modalities.Advances in experimental medicine and biology · 2025Review
- MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions.Cell death & disease · 2024Article
- Review
- An immunohistochemical atlas of necroptotic pathway expression.EMBO molecular medicine · 2024Article
- Type I Interferon: Monkeypox/Mpox Viruses Achilles Heel?Advances in experimental medicine and biology · 2024Review
- RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection.PLoS pathogens · 2023Article
- Virologs, viral mimicry, and virocell metabolism: the expanding scale of cellular functions encoded in the complex genomes of giant viruses.FEMS microbiology reviews · 2023Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Pathogen infection triggers host innate defenses which may result in the activation of regulated cell death (RCD) pathways such as apoptosis. Given a vital role in immunity, apoptotic effectors are often counteracted by pathogen-encoded antagonists. Mounting evidence indicates that programmed necrosis, which is mediated by the RIPK3/MLKL axis and termed necroptosis, evolved as a countermeasure to pathogen-mediated inhibition of apoptosis. Yet, it is unclear whether components of this emerging RCD pathway display signatures associated with pathogen conflict that are rare in combination but common to key host defense factors, namely, rapid evolution, viral homolog (virolog), and cytokine induction. We leveraged evolutionary sequence analysis that examines rates of amino acid replacement, which revealed: 1) strong and recurrent signatures of positive selection for primate and bat RIPK3 and MLKL, and 2) elevated rates of amino acid substitution on multiple RIPK3/MLKL surfaces suggestive of past antagonism with multiple, distinct pathogen-encoded inhibitors. Furthermore, our phylogenomics analysis across poxvirus genomes illuminated volatile patterns of evolution for a recently described MLKL viral homolog. Specifically, poxviral MLKLs have undergone numerous gene replacements mediated by duplication and deletion events. In addition, MLKL protein expression is stimulated by interferons in human and mouse cells. Thus, MLKL displays all three hallmarks of pivotal immune factors of which only a handful of factors like OAS1 exhibit. These data support the hypothesis that over evolutionary time MLKL functions-which may include execution of necroptosis-have served as a major determinant of infection outcomes despite gene loss in some host genomes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.