Dephosphorylation of survival motor neurons (SMN) by PPM1G/PP2Cγ governs Cajal body localization and stability of the SMN complex

Abstract

The survival motor neuron (SMN) complex functions in maturation of uridine-rich small nuclear ribonucleoprotein (RNP) particles. SMN mediates the cytoplasmic assembly of Sm proteins onto uridine-rich small RNAs, and then participates in targeting RNPs to nuclear Cajal bodies (CBs). Recent studies have suggested that phosphorylation might control localization and function of the SMN complex. Here, we show that the nuclear phosphatase PPM1G/PP2Cγ interacts with and dephosphorylates the SMN complex. Small interfering RNA knockdown of PPM1G leads to an altered phosphorylation pattern of SMN and Gemin3, loss of SMN from CBs, and reduced stability of SMN. Accumulation in CBs is restored upon overexpression of catalytically active, but not that of inactive, PPM1G. This demonstrates that PPM1G's phosphatase activity is necessary to maintain SMN subcellular distribution. Concomitant knockdown of unr interacting protein (unrip), a component implicated in cytoplasmic retention of the SMN complex, also rescues the localization defects. Our data suggest that an interplay between PPM1G and unrip determine compartment-specific phosphorylation patterns, localization, and function of the SMN complex.

A role for protein phosphatase PP1γ in SMN complex formation and subnuclear localization to Cajal bodies

“…Other studies involving dephosphorylation of SMN in the nucleoplasm, showed that PP1MG regulates SMN complex stability in CBs (Petri et al, 2007). Consistent with our findings, PP1MG activity is probably not altered in PP1c-depleted cells.…”

“…There are sixteen potential phosphoserines in SMN. It will be interesting to determine whether PP1c targets the same residues as PP1MG and if not, this could explain why depletion of PP1MG decreases SMN localization to CBs (Petri et al, 2007), whereas PP1c depletion increases it.…”

Cajal-body formation correlates with differential coilin phosphorylation in primary and transformed cell lines

“…SMN is a vital component in the cytoplasmic phase of snRNP biogenesis (Meister et al, 2002;Massenet et al, 2002), and might have a role analogous to its cytoplasmic functions in the CB by ensuring that nuclear snRNPs remain functional after a splicing reaction has taken place (Pellizzoni et al, 1998;Xu et al, 2005). Phosphorylation impacts SMN activity and localization (Grimmler et al, 2005;Petri et al, 2007). In particular, dephosphorylation of SMN by the nuclear phosphatase PPM1G is needed for SMN localization to CBs (Petri et al, 2007).…”

“…Phosphorylation impacts SMN activity and localization (Grimmler et al, 2005;Petri et al, 2007). In particular, dephosphorylation of SMN by the nuclear phosphatase PPM1G is needed for SMN localization to CBs (Petri et al, 2007).…”

SMN complexes of nucleus and cytoplasm: A proteomic study for SMA therapy

“…Fibroblast growth factor-2 (FGF-2) competes with gemin2 for binding to SMN and may regulate Cajal body formation [35]. The nuclear phosphatase PPM1G interacts with and dephosphorylates the SMN complex, and in a mechanism that involves unrip, is required to maintain SMN subcellular distribution and stability [36].…”