Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling
Preprint posted on April 02, 2020 https://www.biorxiv.org/content/10.1101/2020.04.02.005041v1
Article now published in Developmental Cell at https://www.cell.com/developmental-cell/fulltext/S1534-5807(20)30757-7
Categories: biochemistry, cell biology, developmental biology, genetics, molecular biology, neuroscience
Context
Serine/arginine-rich proteins (SR proteins), a group of proteins that harbor an arginine/serine (RS) domain either at their N’ or C’ terminus, play crucial roles in a plethora of biological processes such as cell cycle and signaling, developmental pathways, DNA replication and repair, transcription and mRNA splicing. Of note, phosphorylation of SR proteins mediated by Serine/arginine protein kinases (SRPKs) drive their functionality1.
Three mammalian SRPKs – SRPK1, SRPK2, and SRPK3 – relay information between environmental cues and gene expression by regulating SR protein phosphorylation1,2. These kinases have similar nucleotide-binding and active sites (fig.a) and share an overlapping substrate and functional landscape3; intriguingly they also carry out distinct biological functions2. For example, down-regulation or chemical inhibition of SRPK1 effectively blocks angiogenesis by changing the RNA splicing patterns4. Additionally, the C. elegans orthologue of SRPK1 is essential for embryogenesis5, and human SRPK1 is essential for spermatogenesis6. On the other hand, SRPK2 plays a pivotal role in regulating RNA splicing and DNA damage response in neuronal and cancer cells7,8. SPRK3 (predominantly expressed in muscle cells) drives muscle development by regulating muscle-specific mRNA splicing9. However, the authors of the current preprint set out to investigate the non-splicing functions of SRPKs and their potential role in metazoan developmental pathways.
Key outcomes
- The authors identified E3 ubiquitin ligase RNF12 (also known as RLIM) as a potential SRPK substrate using an in silico motif search analysis in the mouse proteome database. The possible reason to choose RNF12 among other candidates could be based on its role in stem cell biology and neural development (the host lab’s previous work10). In this work, their analysis found four serines (S212/S214/S227/S229) adjacent to arginine residues, reminiscent of a classic RS domain (fig.b). Guided by a range of in vitro, in vivo, and mass spectrometry-based studies, they report that these residues are phosphorylated by SRPKs. Interestingly, their mutational analysis demonstrates processive phosphorylation of RNF12 from C’ to N’ direction, a mechanism characteristic of SRPKs11. Moreover, phosphorylation of all four serines – harbored in the nuclear localization signal – supports RNF12 nuclear retention in mouse embryonic stem cells (mESCs).
- They then focused on REX1 (or mouse Zfp42) transcription factor, a canonical downstream substrate of RNF12 that plays a crucial role in X-chromosome inactivation12. RNF12 mediated ubiquitylation of REX1 leads to REX1 protein degradation. Additionally, REX1 levels increased in ubiquitinylation and phosphorylation impaired RNF12 mutant mESCs. Furthermore, SRPK1 and SRPK2 mediated phosphorylation of RNF12 stimulates its ubiquitylation activity in vitro.
- Previous data from the host lab report that functional RNF12 restricts mESC differentiation to neurons10, a finding reinforced in the current study as revealed by gene expression data (RNA-seq and/or qPCR) collected from RNF12 wildtype, phosphorylation, and ubiquitylation impaired mutants. Moreover, RNF12 and SRPK2 are robustly expressed in the adult mouse brain during in vitro neuronal maturation. Additionally, gene expression data from RNF12-REX1 double knockouts reveal REX1 as a key downstream substrate of the SRPK-RNF12 axis to control the neuro-developmental gene expression program.
- Lastly, the authors extended their previously published study of RNF12 mutations that cause Tonne-Kalscheuer Syndrome (TOKAS), a neurodevelopmental disorder, and an X-linked intellectual disability10. In the current work, they found SRPK1 & 2 deletions and SRPK3 variants in patients suffering from intellectual disabilities. They also demonstrate that the same SRPK3 mutations dampen RNF12 phosphorylation reiterating SRPK-RNF12 signaling anomalies in intellectual disability disorders.
Conclusion and Perspective
The current work elegantly reports a novel role of SRPKs in metazoan developmental pathways revealing a novel SRPK-RNF12-REX1 signaling axis in neurodevelopmental pathways (fig.c). This is particularly exciting as SRPK2 seems to play a meaningful role in neurodevelopmental pathways that could be relevant for future studies to unravel the etiology of complex neurological diseases13.
Acknowledgments
I am grateful to all the authors for their support, especially Dr. Greg Findlay and Dr. Francisco Bustos for being open to discuss the work and replying promptly.
References:
- Zhou Z, Fu XD. Regulation of splicing by SR proteins and SR protein-specific kinases. Chromosoma. 2013;122(3):191-207.
- Giannakouros T, Nikolakaki E, Mylonis I, Georgatsou E. Serine-arginine protein kinases: a small protein kinase family with a large cellular presence. FEBS J. 2011;278(4):570-586.
- Varjosalo M, Keskitalo S, Van Drogen A, et al. The protein interaction landscape of the human CMGC kinase group. Cell Rep. 2013;3(4):1306-1320.
- Amin EM, Oltean S, Hua J, et al. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell. 2011;20(6):768-780.
- Galvin BD, Denning DP, Horvitz HR. SPK-1, an SR protein kinase, inhibits programmed cell death in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2011;108(5):1998-2003.
- Papoutsopoulou S, Nikolakaki E, Chalepakis G, Kruft V, Chevaillier P, Giannakouros T. SR protein-specific kinase 1 is highly expressed in testis and phosphorylates protamine 1. Nucleic Acids Res. 1999;27(14):2972-2980.
- Vivarelli S, Lenzken SC, Ruepp MD, et al. Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2. PLoS One. 2013;8(4):e61980. Published 2013 Apr 16.
- Sridhara SC, Carvalho S, Grosso AR, Gallego-Paez LM, Carmo-Fonseca M, de Almeida SF. Transcription Dynamics Prevent RNA-Mediated Genomic Instability through SRPK2-Dependent DDX23 Phosphorylation. Cell Rep. 2017;18(2):334-343.
- Zhang M, Zhu B, Davie J. Alternative splicing of MEF2C pre-mRNA controls its activity in normal myogenesis and promotes tumorigenicity in rhabdomyosarcoma cells. J Biol Chem. 2015;290(1):310-324.
- Bustos F, Segarra-Fas A, Chaugule VK, et al. RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation. Cell Rep. 2018;23(6):1599-1611.
- Ghosh G, Adams JA. Phosphorylation mechanism and structure of serine-arginine protein kinases. FEBS J. 2011;278(4):587-597.
- Gontan C, Mira-Bontenbal H, Magaraki A, et al. REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice. Nat Commun. 2018;9(1):4752. Published 2018 Nov 12.
- Chan CB, Ye K. Serine-arginine protein kinases: new players in neurodegenerative diseases? Rev Neurosci. 2013;24(4):401-413.
Posted on: 22nd September 2020 , updated on: 20th October 2020
doi: https://doi.org/10.1242/prelights.24850
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