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Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive

Suzette N Palmer1, Sruthi Chappidi1, Chelsea Pinkham1

  • 1Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Molecular Biology and Evolution
|August 26, 2021
PubMed

Insights

Host-pathogen conflict drives rapid evolution of necroptosis regulators RIPK3 and MLKL. MLKL exhibits hallmarks of immune factors, suggesting its crucial role in infection outcomes.

Area of Science:

  • Evolutionary biology
  • Immunology
  • Cell biology

Background:

  • Pathogen infection activates host defenses, including regulated cell death (RCD) pathways like apoptosis.
  • Pathogens often encode antagonists to inhibit apoptosis, leading to the evolution of necroptosis (programmed necrosis) mediated by RIPK3/MLKL as a countermeasure.
  • It remains unclear if necroptosis pathway components show signatures of pathogen conflict, such as rapid evolution, viral homologs, and cytokine induction.

Purpose of the Study:

  • To investigate whether RIPK3 and MLKL, key mediators of necroptosis, exhibit evolutionary signatures of host-pathogen conflict.
  • To determine if MLKL possesses characteristics of pivotal immune factors, including rapid evolution, viral homologs, and cytokine induction.

Main Methods:

  • Evolutionary sequence analysis to examine rates of amino acid replacement and identify positive selection.
  • Phylogenomic analysis of poxvirus genomes to study the evolution of MLKL viral homologs.
  • Assessing MLKL protein expression in response to interferons in human and mouse cells.

Main Results:

  • Primate and bat RIPK3 and MLKL show strong and recurrent signatures of positive selection, indicating host-pathogen antagonism.
  • Elevated amino acid substitution rates on RIPK3/MLKL surfaces suggest past interactions with diverse pathogen inhibitors.
  • Poxviral MLKL homologs exhibit rapid evolution via gene replacement, duplication, and deletion.
  • MLKL protein expression is upregulated by interferons in mammalian cells.

Conclusions:

  • MLKL displays all three hallmarks of pivotal immune factors, similar to OAS1.
  • These findings support the hypothesis that MLKL's functions, including necroptosis execution, have significantly influenced infection outcomes throughout evolution.
  • Despite gene loss in some genomes, MLKL remains a critical factor in host defense against pathogens.
Keywords:
MLKLRIPK3necroptosisphylogeneticspoxvirussynteny

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