Hdac7-Derived 7aa Peptide May Function As A Phosphorylation Carrier

Background: Histone deacetylase 7 (HDAC7) belongs to class II HDAC family, playing a pivotal role in the maintenance of endothelium integrity. There are 8 splicing variants in mouse HDAC7 mRNAs. Within the 5’ terminal non-coding area of some variants, there exist some short open reading frames (sORFs). Whether these sORFs can be translated and their potential roles in cellular physiology remain unclear. Method and results: Our previous studies suggested that one mouse HDAC7 produced a 7aa peptide from the non-coding area. In this study, we demonstrated that one sORF encoding a 7 amino acids (aa)-peptide could be translated in response to vascular endothelial cell growth factor (VEGF) in vascular progenitor cells (VPCs). The 7aa-peptide (7A) could be phosphorylated at serine residue via MEKK1. Importantly, the phosphorylated 7aa-peptide (7Ap) could transfer the phosphorylation group to the Thr residue of the 14-3-3γ protein in a cell free in-gel buffer system. The in vitro functional analyses revealed that 7A enhanced VEGF-induced VPC migration and differentiation toward endothelial cell (EC) lineage, in which MEKK1 and 14-3-3γ served as upstream kinase and downstream effector respectively. Knockdown of either MEKK1 or 14-3-3γ attenuated VEGF-induced VPC migration and differentiation. Exogenous 7Ap could rescue VEGF effect in MEKK1 but not in 14-3-3γ knockdown cells. The in vivo studies showed that 7A especially 7Ap induced capillary vessel formation within matrigel plug assays, increased re-endothelialization and suppressed neointima formation in the femoral artery injury model, and promoted the foot blood perfusion recovery in the hindlimb ischemia model. Conclusion: These results indicate that the sORFs within the non-coding area can be translated under some circumstances and that the 7aa-peptide may play an important role in cellular processes like migration and differentiation via acting as a phosphorylation carrier. Significance: As a phosphorylation carrier, 7aa possesses therapeutic potentials in tackling angiogenesis related diseases.