Influence of Sox protein SUMOylation on neural development and regeneration

Abstract

SRY-related HMG-box (Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases. Post-translational modification of Sox proteins is known to alter their functions in the central nervous system. Among the different types of post-translational modification, small ubiquitin-like modifier (SUMO) modification of Sox proteins has been shown to modify their transcriptional activity. Here, we review the mechanisms of three Sox proteins in neuronal development and disease, along with their transcriptional changes under SUMOylation. Across three species, lysine is the conserved residue for SUMOylation. In Drosophila, SUMOylation of SoxN plays a repressive role in transcriptional activity, which impairs central nervous system development. However, deSUMOylation of SoxE and Sox11 plays neuroprotective roles, which promote neural crest precursor formation in Xenopus and retinal ganglion cell differentiation as well as axon regeneration in the rodent. We further discuss a potential translational therapy by SUMO site modification using AAV gene transduction and Clustered regularly interspaced short palindromic repeats-Cas9 technology. Understanding the underlying mechanisms of Sox SUMOylation, especially in the rodent system, may provide a therapeutic strategy to address issues associated with neuronal development and neurodegeneration.

Keywords: SUMOylation; Sox transcription factor; axon regeneration; neural development; neurological disorder; neuroprotection; post-translational modification; small ubiquitin-like modifier.

Figure 1

DeSUMOylation of Sox11 by lysine 91 (K91) mutation promotes RGC differentiation and axon regeneration but reduces α-RGC and ipRGC expression in Murinae. ipRGC: Intrinsically photosensitive retinal ganglion cell; Sox: SRY-related HMG-box; SUMO: small ubiquitin-like modifier. Created with BioRender.com.

Figure 2

SUMOylation of Sox9 on lysine 61 and 365 (K61, 365) represses transcriptional activity by recruiting repressor Grg4 to form an inhibitory complex, which suppresses neural crest formation but promotes inner ear development in Xenopus. Grg4: Groucho-related gene 4; Sox: SRY-related HMG-box; SUMO: small ubiquitin-like modifier. Created with BioRender.com.

Figure 3

SUMOylation of SoxN on lysine 439 (K439) suppresses transcriptional activity, which prevents CNS from impairment in Drosophila. CNS: Central nervous system; Sox: SRY-related HMG-box; SUMO: small ubiquitin-like modifier. Created with BioRender.com.