Nuclear Inhibitor of Protein Phosphatase-1 (NIPP1) Directs Protein Phosphatase-1 (PP1) to Dephosphorylate the U2 Small Nuclear Ribonucleoprotein Particle (snRNP) Component, Spliceosome-associated Protein 155 (Sap155)

Pre-mRNA splicing entails reversible phosphorylation of spliceosomal proteins. Recent work has revealed essential roles for Ser/Thr phosphatases, such as protein phosphatase-1 (PP1), in splicing, but how these phosphatases are regulated is largely unknown. We show that nuclear inhibitor of PP1 (NIPP...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-12, Vol.283 (51), p.35805-35814
Main Authors: Tanuma, Nobuhiro, Kim, Sei-Eun, Beullens, Monique, Tsubaki, Yao, Mitsuhashi, Shinya, Nomura, Miyuki, Kawamura, Takeshi, Isono, Kyoichi, Koseki, Haruhiko, Sato, Masami, Bollen, Mathieu, Kikuchi, Kunimi, Shima, Hiroshi
Format: Article
Language:English
Subjects:
Endoribonucleases - genetics
Endoribonucleases - metabolism
Gene Knockdown Techniques
HeLa Cells
Humans
Phosphoprotein Phosphatases - genetics
Phosphoprotein Phosphatases - metabolism
Phosphoproteins - genetics
Phosphoproteins - metabolism
Phosphorylation - physiology
Protein Phosphatase 1 - genetics
Protein Phosphatase 1 - metabolism
Protein Structure, Tertiary - physiology
Ribonucleoprotein, U2 Small Nuclear - genetics
Ribonucleoprotein, U2 Small Nuclear - metabolism
RNA Precursors - genetics
RNA Precursors - metabolism
RNA Splicing - physiology
RNA Splicing Factors
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
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Summary:Pre-mRNA splicing entails reversible phosphorylation of spliceosomal proteins. Recent work has revealed essential roles for Ser/Thr phosphatases, such as protein phosphatase-1 (PP1), in splicing, but how these phosphatases are regulated is largely unknown. We show that nuclear inhibitor of PP1 (NIPP1), a major PP1 interactor in the vertebrate nucleus, recruits PP1 to Sap155 (spliceosome-associated protein 155), an essential component of U2 small nuclear ribonucleoprotein particles, and promotes Sap155 dephosphorylation. C-terminally truncated NIPP1 (NIPP1-ΔC) formed a hyper-active holoenzyme with PP1, rendering PP1 minimally phosphorylated on an inhibitory site. Forced expression of NIPP1-WT and -ΔC resulted in slight and severe decreases in Sap155 hyperphosphorylation, respectively, and the latter was accompanied with inhibition of splicing. PP1 overexpression produced similar effects, whereas small interfering RNA-mediated NIPP1 knockdown enhanced Sap155 hyperphosphorylation upon okadaic acid treatment. NIPP1 did not inhibit but rather stimulated Sap155 dephosphorylation by PP1 in vitro through facilitating Sap155/PP1 interaction. Further analysis revealed that NIPP1 specifically recognizes hyperphosphorylated Sap155 thorough its Forkhead-associated domain and dissociates from Sap155 after dephosphorylation by associated PP1. Thus NIPP1 works as a molecular sensor for PP1 to recognize phosphorylated Sap155.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M805468200