Article ; Online: Pyruvate Kinase M (PKM) binds ribosomes in a poly-ADP ribosylation dependent manner to induce translational stalling.
2023 Volume 51, Issue 12, Page(s) 6461–6478
Abstract: In light of the numerous studies identifying post-transcriptional regulators on the surface of the endoplasmic reticulum (ER), we asked whether there are factors that regulate compartment specific mRNA translation in human cells. Using a proteomic survey ...
Abstract | In light of the numerous studies identifying post-transcriptional regulators on the surface of the endoplasmic reticulum (ER), we asked whether there are factors that regulate compartment specific mRNA translation in human cells. Using a proteomic survey of spatially regulated polysome interacting proteins, we identified the glycolytic enzyme Pyruvate Kinase M (PKM) as a cytosolic (i.e. ER-excluded) polysome interactor and investigated how it influences mRNA translation. We discovered that the PKM-polysome interaction is directly regulated by ADP levels-providing a link between carbohydrate metabolism and mRNA translation. By performing enhanced crosslinking immunoprecipitation-sequencing (eCLIP-seq), we found that PKM crosslinks to mRNA sequences that are immediately downstream of regions that encode lysine- and glutamate-enriched tracts. Using ribosome footprint protection sequencing, we found that PKM binding to ribosomes causes translational stalling near lysine and glutamate encoding sequences. Lastly, we observed that PKM recruitment to polysomes is dependent on poly-ADP ribosylation activity (PARylation)-and may depend on co-translational PARylation of lysine and glutamate residues of nascent polypeptide chains. Overall, our study uncovers a novel role for PKM in post-transcriptional gene regulation, linking cellular metabolism and mRNA translation. |
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MeSH term(s) | Humans ; Glutamates/analysis ; Glutamates/genetics ; Glutamates/metabolism ; Lysine/metabolism ; Poly ADP Ribosylation ; Protein Biosynthesis ; Proteomics ; Pyruvate Kinase/genetics ; Pyruvate Kinase/analysis ; Pyruvate Kinase/metabolism ; Ribosomes/metabolism |
Chemical Substances | Glutamates ; Lysine (K3Z4F929H6) ; Pyruvate Kinase (EC 2.7.1.40) |
Language | English |
Publishing date | 2023-05-24 |
Publishing country | England |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 186809-3 |
ISSN | 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048 |
ISSN (online) | 1362-4962 ; 1362-4954 |
ISSN | 0301-5610 ; 0305-1048 |
DOI | 10.1093/nar/gkad440 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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