ALKBH4-dependent demethylation of actin regulates actomyosin dynamics

Abstract

Regulation of actomyosin dynamics by post-transcriptional modifications in cytoplasmic actin is still poorly understood. Here we demonstrate that dioxygenase ALKBH4-mediated demethylation of a monomethylated site in actin (K84me1) regulates actin–myosin interaction and actomyosin-dependent processes such as cytokinesis and cell migration. ALKBH4-deficient cells display elevated K84me1 levels. Non-muscle myosin II only interacts with unmethylated actin and its proper recruitment to and interaction with actin depend on ALKBH4. ALKBH4 co-localizes with the actomyosin-based contractile ring and midbody via association with methylated actin. ALKBH4-mediated regulation of actomyosin dynamics is completely dependent on its catalytic activity. Disorganization of cleavage furrow components and multinucleation associated with ALKBH4 deficiency can all be restored by reconstitution with wild-type but not catalytically inactive ALKBH4. Similar to actin and myosin knock-out mice, homozygous Alkbh4 mutant mice display early embryonic lethality. These findings imply that ALKBH4-dependent actin demethylation regulates actomyosin function by promoting actin-non-muscle myosin II interaction.

The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond

“…ALKBH8 (50 -54) is involved in the maturation of tRNA featuring both an S-adenosylmethionine-dependent methyltransferase domain that methylates 5-carboxymethyluridine (cm5U) to 5-methoxycarbonylmethyluridine (mcm5U), and a dioxygenase domain that hydroxylates mcm5U to generate (S)-5-methoxycarbonylhydroxymethyluridine (mchm5U), a common functional modification at the wobble position of tRNA (51,52). The main function of ALKBH4 seems to be actin demethylation (55,56). ALKBH7, which plays a role in alkylationinduced necrosis (57)(58)(59), is believed to act on protein substrates, but their identity is not currently known.…”

Structures of Human ALKBH5 Demethylase Reveal a Unique Binding Mode for Specific Single-stranded N6-Methyladenosine RNA Demethylation

“…The human AlkB family comprises nine members: ALKBH1-8 and FTO; the family is named after their Escherichia coli ortholog, AlkB (20 (24,25); ALKBH4 regulates the demethylation of actin (26); ALKBH7 is involved with the programmed cell necrosis, although a nucleic acid demethylase activity for it has yet to be reported (27); ALKBH8 was demonstrated to hydroxylate 5-methoxycarbonylmethyluridine in tRNA (28); and FTO prefers both m 3 T ssDNA and m 6 A ssRNA (9,29). ALKBH5 is reported to catalyze N-demethylation of m 6 A ssRNA or ssDNA, but not other tested modified nucleotides (8,30).…”

WD Repeat-containing Protein 5 (WDR5) Localizes to the Midbody and Regulates Abscission

“…It is also possible that an H3K4MT methyltransferase complex or subcomplex promotes abscission by methylating novel non-histone midbody substrate(s). The recent observation that a midbody-localized demethylase ALKBH4 facilitates cytokinesis by demethylating actin at the cleavage furrow suggests that regulated methylation/demethylation of non-histone proteins may be important for proper cytokinesis (66).…”