The role of survival motor neuron protein (SMN) in protein homeostasis

Abstract

Ever since loss of survival motor neuron (SMN) protein was identified as the direct cause of the childhood inherited neurodegenerative disorder spinal muscular atrophy, significant efforts have been made to reveal the molecular functions of this ubiquitously expressed protein. Resulting research demonstrated that SMN plays important roles in multiple fundamental cellular homeostatic pathways, including a well-characterised role in the assembly of the spliceosome and biogenesis of ribonucleoproteins. More recent studies have shown that SMN is also involved in other housekeeping processes, including mRNA trafficking and local translation, cytoskeletal dynamics, endocytosis and autophagy. Moreover, SMN has been shown to influence mitochondria and bioenergetic pathways as well as regulate function of the ubiquitin-proteasome system. In this review, we summarise these diverse functions of SMN, confirming its key role in maintenance of the homeostatic environment of the cell.

Keywords: Bioenergetic pathway; Cytoskeleton; Ribonucleoprotein; Spinal muscular atrophy; Translation; Ubiquitin.

Fig. 1

Schematic overview of the alterations in cytoskeletal dynamics and endocytosis observed following SMN deficiency. The diagram highlights these changes at the level of the motor neuron and neuromuscular junction. All changes associated with SMN loss are represented in dark blue. SMN deficiency results in a decrease in cellular transport (e.g. synaptic vesicle, RNA granules and mitochondria) and endocytosis. In the absence of SMN, not only a destabilisation of the microtubules is observed, but also a depolymerisation of the actin cytoskeleton, which has been linked to the activation of the RhoA/ROCK pathway

Fig. 2

Diagrammatic representation of the ubiquitin pathway and the components, where SMN interacts. SMN is both ubiquitinated via the UPS pathway and an interacting protein influencing several steps of the process. SMN directly interacts with the UBA1 enzyme, which transfers ubiquitin to the E2 ligases. Ubiquitinated E2 ligases then form a complex with E3 ligases bound to protein substrates. SMN has been shown to interact with several E3 ligases, including Mindbomb 1, Itch and TRAF6. Ubiquitin is then transferred to the protein substrate and the complex dissociates. Monoubiquitinated substrates continue on to other intracellular processes, whereas polyubiquitinated substrates are targeted for proteasome degradation. SMN has also been shown to interact with deubiquitinating enzymes, which remove ubiquitin from protein substrates