ArticleBioscience reports2015
Analysis of the N-terminal region of human MLKL, as well as two distinct MLKL isoforms, reveals new insights into necroptotic cell death.
Article in Bioscience reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Article
- Tumor necrosis factor is a necroptosis-associated alarmin.Frontiers in immunology · 2022Article
- Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis.Molecules (Basel, Switzerland) · 2021Article
- Review
- TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response.Cell reports · 2021Article
- The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis.Journal of molecular cell biology · 2021Review
- Reconstitution of Human Necrosome Interactions inBiomolecules · 2021Article
- Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Pore formation in regulated cell death.The EMBO journal · 2020Review
- In vitro analysis reveals necroptotic signaling does not provoke DNA damage or HPRT mutations.Cell death & disease · 2020Article
- A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.Nature communications · 2020Article
- MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis.Nature communications · 2020Article
- Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.Cell chemical biology · 2019Article
- Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.Nature communications · 2018Article
- Insane in the membrane: a structural perspective of MLKL function in necroptosis.Immunology and cell biology · 2017Review
- MLKL forms cation channels.Cell research · 2016Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential effector of necroptotic cell death. Two distinct human MLKL isoforms have previously been reported, but their capacities to trigger cell death have not been compared directly. Herein, we examine these two MLKL isoforms, and further probe the features of the human MLKL N-terminal domain that are required for cell death. Expression in HEK293T cells of the N-terminal 201 amino acids (aa) of human MLKL is sufficient to cause cell death, whereas expression of the first 154 aa is not. Given that aa 1-125 are able to initiate necroptosis, our findings indicate that the helix that follows this region restrains necroptotic activity, which is again restored in longer constructs. Furthermore, MLKL isoform 2 (MLKL2), which lacks much of the regulatory pseudokinase domain, is a much more potent inducer of cell death than MLKL isoform 1 (MLKL1) in ectopic expression studies in HEK293T cells. Modelling predicts that a C-terminal helix constrains the activity of MLKL1, but not MLKL2. Although both isoforms are expressed by human monocyte-derived macrophages at the mRNA level, MLKL2 is expressed at much lower levels. We propose that it may have a regulatory role in controlling macrophage survival, either in the steady state or in response to specific stimuli.
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