A Ca2+-Dependent Switch Activates Axonal Casein Kinase 2α Translation and Drives G3BP1 Granule Disassembly for Axon Regeneration

Oct 16, 2020Current biology : CB

Calcium-Triggered Activation of a Protein Kinase Boosts Protein Production and Breaks Down Granules to Support Nerve Fiber Regeneration

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Abstract

G3BP1 phosphorylation by casein kinase 2α (CK2α) may accelerate nerve regeneration in the peripheral nervous system.

CK2α activity is regulated by local translation of Csnk2a1 mRNA in axons after injury.
Disassembly of G3BP1 granules in injured axons is associated with increased phospho-G3BP1 and axon growth.
Depletion of Csnk2a1 mRNA from PNS axons leads to decreased regeneration and increased G3BP1 granules.
Phosphomimetic G3BP1 exhibits reduced RNA binding in dorsal root ganglion neurons compared to wild-type G3BP1.
Axoplasmic calcium concentrations influence the timing of translational activation of different axonal mRNAs during regeneration.

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The main limitation on axon regeneration in the peripheral nervous system (PNS) is the slow rate of regrowth. We recently reported that nerve regeneration can be accelerated by axonal G3BP1 granule disassembly, releasing axonal mRNAs for local translation to support axon growth. Here, we show that G3BP1 phosphorylation by casein kinase 2α (CK2α) triggers G3BP1 granule disassembly in injured axons. CK2α activity is temporally and spatially regulated by local translation of Csnk2a1 mRNA in axons after injury, but this requires local translation of mTor mRNA and buffering of the elevated axonal Cathat occurs after axotomy. CK2α's appearance in axons after PNS nerve injury correlates with disassembly of axonal G3BP1 granules as well as increased phospho-G3BP1 and axon growth, although depletion of Csnk2a1 mRNA from PNS axons decreases regeneration and increases G3BP1 granules. Phosphomimetic G3BP1 shows remarkably decreased RNA binding in dorsal root ganglion (DRG) neurons compared with wild-type and non-phosphorylatable G3BP1; combined with other studies, this suggests that CK2α-dependent G3BP1 phosphorylation on Ser 149 after axotomy releases axonal mRNAs for translation. Translation of axonal mRNAs encoding some injury-associated proteins is known to be increased with Caelevations, and using a dual fluorescence recovery after photobleaching (FRAP) reporter assay for axonal translation, we see that translational specificity switches from injury-associated protein mRNA translation to CK2α translation with endoplasmic reticulum (ER) Carelease versus cytoplasmic Cachelation. Our results point to axoplasmic Caconcentrations as a determinant for the temporal specificity of sequential translational activation of different axonal mRNAs as severed axons transition from injury to regenerative growth. 2+ 2+ 2+ 2+ 2+

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A Ca2+-Dependent Switch Activates Axonal Casein Kinase 2α Translation and Drives G3BP1 Granule Disassembly for Axon Regeneration

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