Chaperoning ribonucleoprotein biogenesis in health and disease

Abstract

The survival motor neuron (SMN) protein is part of a macromolecular complex that functions in the biogenesis of small nuclear ribonucleoproteins (snRNPs)--the essential components of the pre-messenger RNA splicing machinery--as well as probably other RNPs. Reduced levels of SMN expression cause the inherited motor neuron disease spinal muscular atrophy (SMA). Knowledge of the composition, interactions and functions of the SMN complex has advanced greatly in recent years. The emerging picture is that the SMN complex acts as a macromolecular chaperone of RNPs to increase the efficiency and fidelity of RNA-protein interactions in vivo, and to provide an opportunity for these interactions to be regulated. In addition, it seems that RNA metabolism deficiencies underlie SMA. Here, a dual dysfunction hypothesis is presented in which two mechanistically and temporally distinct defects--that are dependent on the extent of SMN reduction in SMA--affect the homeostasis of specific messenger RNAs encoding proteins essential for motor neuron development and function.

Figure 1

Schematic illustration of the survival motor neuron (SMN) complex. The survival motor neuron (SMN) protein binds Gemin2, Gemin3, Gemin5, Gemin7 and Gemin8, whereas Gemin4 and Gemin6 associate with SMN through interactions with Gemin3 and Gemin7, respectively. Gemin8 also binds the Gemin6–Gemin7 heterodimer, and mediates the association of Gemin6, Gemin7 and unrip with SMN. The SMN protein oligomerizes and, for simplicity, is depicted as a trimer although it can form much larger oligomeric structures (Pellizzoni et al, 1999). The representation of the SMN complex is an arbitrary simplification because the stoichiometry of its components is unknown.

Figure 2

The small nuclear ribonucleoprotein biogenesis pathway. RNA polymerase II transcribes snRNAs as precursors containing an m7G cap and short 3′-end extensions in the nucleus. The cap-binding complex (CBC) binds nascent snRNAs and mediates the recruitment of the phosphorylated adaptor for RNA export (PHAX), exportin 1 (Xpo1) and ras-related nuclear protein GTP (RanGTP) for nuclear export. In the cytoplasm, the seven Sm proteins bind first to the chloride conductance regulatory protein (pICln) and the protein arginine methyltransferase 5 (PRMT5) complex—which symmetrically dimethylates SmB, SmD1 and SmD3—and then to the survival motor neuron (SMN) complex. The SMN complex bound to the Sm proteins interacts with snRNAs and mediates Sm core assembly. Hypermethylation of the 5′ cap of snRNAs by trimethylguanosine synthase 1 (TGS1) occurs after Sm core formation; both the SMN complex and snurportin, which associates with the 5′ cap of snRNAs, then bind to importin-β and mediate snRNP nuclear import. The SMN complex and snRNPs transiently localize to Cajal bodies, in which snRNPs undergo further maturation steps including methylation and pseudo-uridylation by small Cajal body-specific ribonucleoproteins (scaRNPs), before functioning in pre-messenger RNA splicing. Depending on the cell type and developmental stage, the SMN complex also localizes to Gems. snRNP, small nuclear ribonucleoprotein.

Figure 3

Developmental regulation of the survival motor neuron complex activity in the spinal cord. The graph shows the relative levels of small nuclear ribonucleoprotein (snRNP) assembly activity during spinal cord development. Spinal cords were isolated from embryos at embryonic day 18 (E18) as well as from mice at the indicated postnatal ages, SMN activity was then analysed in snRNP assembly experiments with in vitro-transcribed radioactive U1 snRNA and tissue extracts normalized for equal SMN content (Gabanella et al, 2005). The levels of U1 snRNP assembled in these reactions were quantified and expressed as a percentage of that of embryos at E18 arbitrarily set as 100%. d, day; SMN, survival motor neuron; w, week.

Livio Pellizzoni