What is it about?
This study demonstrated a potential role of the enzyme Pyruvate Kinase M2 (PKM2) in blocking cell death mediated by the mitochondrial apoptosis pathway. We expressed a library of intracellular scFv antibodies (intrabodies) in cultured cells and then selected for intrabodies that could block apoptotic cell death. We identified one such intrabody that bound selectively to PKM2. In addition to blocking mitochondria-mediated apoptosis, the intrabody caused PKM2 tetramerization and an increased glycolytic activity of PKM2. The intrabody-PKM2 interaction caused the upregulation of Mitofusin1 (MFN1), a protein required for mitochondrial fusion, and MFN1 was required for protection against cell death. We hypothesize that the intrabody mimics an unidentified cellular protein that interacts with PKM2 to inhibit apoptosis.
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Why is it important?
The anti-apoptotic activity of tetrameric PKM2 could play a role in the survival of slowly dividing cell populations, such as cancer stem cells.
Perspectives
This study provides an intriguing connection between a glycolytic enzyme, PKM2, the mitochondrial fusion-related protein MFN1, and the core mitochondrial apoptosis pathway regulated by BCL-2-family proteins. Further research will be needed to identify the potential cellular interaction partner of PKM2 that might engage this function, as well as to identify cell populations affected. The potential PKM2 interaction partner could prove to be a therapeutic target in certain diseases.
Donald Newmeyer
La Jolla Institute for Allergy and Immunology
Read the Original
This page is a summary of: Phenotypic selection with an intrabody library reveals an anti-apoptotic function of PKM2 requiring Mitofusin-1, PLoS Biology, June 2019, PLOS,
DOI: 10.1371/journal.pbio.2004413.
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