Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 34; pp. E7092 - E7100
• Main Authors: Krapivinsky, Grigory, Krapivinsky, Luba, Renthal, Nora E., Santa-Cruz, Ana, Manasian, Yunona, Clapham, David E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.08.2017
• Series: PNAS Plus
• Subjects: Amino acids; Arginine; Arginine - chemistry; Arginine - genetics; Arginine - metabolism; Biological Sciences; Cell Line; Clonal deletion; Conductance; Deactivation; DNA methylation; Gene deletion; Gene expression; Gene Expression Regulation; Histones - chemistry; Histones - genetics; Histones - metabolism; Humans; Inactivation; Ion channels; Ions; Kinases; Methylation; Nuclei; Phosphorylation; PNAS Plus; Polypeptides; Protein arginine methyltransferase; Protein Domains; Protein-serine/threonine kinase; Residues; Resistance; Serine - genetics; Serine - metabolism; Studies; Threonine - genetics; Threonine - metabolism; Transcription; Transient receptor potential proteins; TRPM Cation Channels - chemistry; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism; PRMT5; kinase; TRPM7; ion channel; TRPM6
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1708427114

TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating histone arginine residues. Histone phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in histone S/T phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific histone phosphorylation. M6CK histone phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.