The TRPM7 Chanzyme Is Cleaved to Release a Chromatin-Modifying Kinase

Abstract

SUMMARY TRPM7 is a ubiquitous ion channel and kinase, a unique ‘chanzyme’, required for proper early embryonic development. It conducts Zn2+, Mg2+, Ca2+ as well as monovalent cations, and contains a functional serine/threonine kinase at its carboxyl terminus. Here, we show that in normal tissues and cell lines, the kinase is proteolytically cleaved from the channel domain in a cell type-specific manner. These TRPM7 Cleaved Kinase fragments (M7CKs) translocate to the nucleus and bind multiple components of chromatin remodeling complexes, including Polycomb group proteins. In the nucleus, the kinase phosphorylates specific serines/threonines of histones. M7CK-dependent phosphorylation of H3Ser10 at promoters of TRPM7-dependent genes correlates with their activity. We also demonstrate that cytosolic free [Zn2+] is TRPM7-dependent and regulates M7CK binding to transcription factors containing zinc-finger domains. These findings suggest that TRPM7-mediated modulation of intracellular Zn2+ concentration couples ion channel signaling to epigenetic chromatin covalent modifications that affect gene expression patterns.

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

“…Covalently bound zinc is required for the activity of numerous enzymes and transcription factors (28). The zinc finger is an ancient structural motif capable of interacting with both DNA and RNA, and proteins containing this motif are the most-abundant class of proteins in the human proteome (29 transporters (30,(34)(35)(36). Synaptic Zn 2+ plays an essential role in modulating synaptic transmission throughout the brain (37-40), including the retina, where it contributes to neuromodulation and neuroprotection (41, 42).…”

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

“…Like the endoplasmic reticulum, these vesicles are a distributed system for divalent cation uptake and release, but in this case the primary divalent ion is Zn 2+ rather than Ca , an ion channel and cytoplasmic kinase, is ubiquitously expressed and essential in early embryonic development (1-4) but also may mediate oxidative stress-induced anoxic neuronal death in adults (5,6). As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8). TRPM7's C-terminal kinase can phosphorylate multiple substrates (11)(12)(13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14).…”

“…As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8). TRPM7's C-terminal kinase can phosphorylate multiple substrates (11)(12)(13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14). Zn 2+ regulates TRPM7's kinase activity (11) and binding to transcription factors (8).…”

“…TRPM7's C-terminal kinase can phosphorylate multiple substrates (11)(12)(13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14). Zn 2+ regulates TRPM7's kinase activity (11) and binding to transcription factors (8). It is a potent signal for many cellular processes previously related to TRPM7 function, including gene expression, mitosis, and cell survival, but is also proapoptotic at extreme concentrations (15)(16)(17)(18).…”

Characterization of the Catalytic and Nucleotide Binding Properties of the α-Kinase Domain of Dictyostelium Myosin-II Heavy Chain Kinase A

“…The transient receptor potential melastatin-like 7 (TRPM7) ion channel contains a C-terminal ␣-kinase domain that, like MHCK-A, regulates myosin-II filament assembly (16,17). Proteolytic cleavage of the ␣-kinase domain from TRPM7 allows the kinase domain to translocate to the nucleus, phosphorylate histones, and regulates gene expression (18).…”