Small noncoding vault RNA modulates synapse formation by amplifying MAPK signaling

Abstract

The small noncoding vault RNA (vtRNA) is a component of the vault complex, a ribonucleoprotein complex found in most eukaryotes. Emerging evidence suggests that vtRNAs may be involved in the regulation of a variety of cellular functions when unassociated with the vault complex. Here, we demonstrate a novel role for vtRNA in synaptogenesis. Using an in vitro synapse formation model, we show that murine vtRNA (mvtRNA) promotes synapse formation by modulating the MAPK signaling pathway. mvtRNA is transported to the distal region of neurites as part of the vault complex. Interestingly, mvtRNA is released from the vault complex in the neurite by a mitotic kinase Aurora-A–dependent phosphorylation of MVP, a major protein component of the vault complex. mvtRNA binds to and activates MEK1 and thereby enhances MEK1-mediated ERK activation in neurites. These results suggest the existence of a regulatory mechanism of the MAPK signaling pathway by vtRNAs as a new molecular basis for synapse formation.

Novel Molecular Basis for Synapse Formation: Small Non-coding Vault RNA Functions as a Riboregulator of MEK1 to Modulate Synaptogenesis

“…To understand the function of released mvtRNA, we examined how it affected ERK activity-dependent synaptogenesis. In neurites with RNAimediated downregulation of mvp or antisense oligonucleotidemediated downregulation of mvtRNA, we observed reduced ERK activation, local translation and synaptic formation (Wakatsuki et al, 2021b). These results suggest that mvtRNA acts on ERK activity to potentiate local translation in neurites and positively regulate synaptogenesis (Figure 1).…”

“…We also confirmed the functionality of the increased synapses in response to the Aurora-A-MVP signaling by an increase of FM dye uptake into synaptic vesicles and glutamate-stimulated intracellular calcium ion concentrations. These results indicate that enhancement of the Aurora-A-MVP pathway promotes functional synaptogenesis (Wakatsuki et al, 2021b).…”

“…Subsequently, Aurora-A was also found in non-dividing neurons and has recently been reported to play an important role in the regulation of neuronal morphological differentiation, including neurite outgrowth and polarity formation (Khazaei and Puschel, 2009;Mori et al, 2009;Pollarolo et al, 2011). To clarify the details of Aurora-A dependent processes in neurons, we screened substrates for Aurora-A kinase activity in neurons and found MVP as a prime candidate (Wakatsuki et al, 2021b). We found that the expression level of MVP expression in the brain and the degree of Aurora-A-MVP interaction in the postsynaptic region increase with development and remain stable in maturity.…”

“…These results suggest that the vault complex may function as a transporter for both mRNAs translated in dendrites and Aurora-A, which are both involved in the regulation of local translation. In fact, the vault complex was found to bind to the dendritic transport motor protein KIF5 (Hirokawa, 2006;Wakatsuki et al, 2021b), suggesting that the vault complex is transported in dendrites as cargo of KIF5.…”

“…to phosphorylate ERK (Wakatsuki et al, 2021b). Extensive knowledge has been accumulated about the relationship between molecular structure and MEK activity; and the changes in molecular structure during the MEK activating process have been investigated in detail.…”