Abstract
Spinal muscular atrophy (SMA) is caused by homozygous loss of human SMN1 (survival motor neuron 1). Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein, called SMN∆7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of SMN protein isoforms are poorly understood. We used a Drosophila model system and ‘label-free’ proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. We show that this interaction is conserved from fly to human, and that SCFSlmb interacts with a phospho-degron embedded within the SMN YG-box self- oligomerization domain. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and greatly stabilizes SMN∆7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Furthermore, overexpression of SMN∆7S270A, but not wild-type SMN∆7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the SCFSlmb degron is largely exposed when SMN is monomeric, whereas it is sequestered when SMN forms higher-order multimers. SMN stability is thus regulated by self-oligomerization, providing an elegant mechanism for balancing functional activity.