Sumoylation regulates the assembly and activity of the SMN complex

Giulietta M Riboldi,Stefania Corti,Paola Rinchetti,Irene Faravelli,Georgia Dermentzaki,Francesco Lotti,George Z Mentis,Nicolas Delestrée,Le Thi Hao,Serge Przedborski,Takaaki Kuwajima,Christine C Beattie,Mariangels De Planell-Saguer

doi:10.1038/s41467-021-25272-5

Abstract

SMN is a ubiquitously expressed protein and is essential for life. SMN deficiency causes the neurodegenerative disease spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. SMN interacts with itself and other proteins to form a complex that functions in the assembly of ribonucleoproteins. SMN is modified by SUMO (Small Ubiquitin-like Modifier), but whether sumoylation is required for the functions of SMN that are relevant to SMA pathogenesis is not known. Here, we show that inactivation of a SUMO-interacting motif (SIM) alters SMN sub-cellular distribution, the integrity of its complex, and its function in small nuclear ribonucleoproteins biogenesis. Expression of a SIM-inactivated mutant of SMN in a mouse model of SMA slightly extends survival rate with limited and transient correction of motor deficits. Remarkably, although SIM-inactivated SMN attenuates motor neuron loss and improves neuromuscular junction synapses, it fails to prevent the loss of sensory-motor synapses. These findings suggest that sumoylation is important for proper assembly and function of the SMN complex and that loss of this post-translational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of SMA mice.

Highlights

Survival of motor neuron (SMN) is a ubiquitously expressed protein and is essential for life
We found that inhibition of sumoylation results in a redistribution of SMN from the nucleus to the cytoplasm (Supplementary Fig. 1d and 1e), suggesting that the altered localization of SMN observed in these cells upon UBC9 depletion is due to an impaired nuclear transport
In addition to being sumoylated, SMN can interact with Small ubiquitin-like modifier (SUMO) through its SUMO-interacting motif (SIM)

Summary

Introduction

SMN is a ubiquitously expressed protein and is essential for life. SMN deficiency causes the neurodegenerative disease spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. We show that inactivation of a SUMO-interacting motif (SIM) alters SMN sub-cellular distribution, the integrity of its complex, and its function in small nuclear ribonucleoproteins biogenesis. SIM-inactivated SMN attenuates motor neuron loss and improves neuromuscular junction synapses, it fails to prevent the loss of sensory-motor synapses These findings suggest that sumoylation is important for proper assembly and function of the SMN complex and that loss of this post-translational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of SMA mice. SMN associates with itself and at least eight additional proteins (GEMIN2-8 and UNRIP) to form the SMN complex[3,4] This multimeric complex has a wellcharacterized role in the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs)[5,6] as well as U7 snRNP that functions in the 3′ end processing of histone mRNAs7,8. SUMO modification has been shown to promote the nuclear import of polo-like kinase 1 (PLK1) and to prevents its proteasomal degradation[33]

Methods

Results

Conclusion