The catalytically inactive tyrosine phosphatase HD-PTP/PTPN23 is a novel regulator of SMN complex localization
The catalytically inactive tyrosine phosphatase HD-PTP/PTPN23 is a novel regulator of SMN complex localization
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DOI：
10.1091/mbc.e14-06-1151
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发表时间：
2015-01-15
影响因子：
3.3
通讯作者：
Gruss, Oliver J.
中科院分区：
文献类型：
--
作者：
Husedzinovic, Alma;Neumann, Beate;Gruss, Oliver J.
存活运动神经元（SMN）复合体在snRNPs的组装中发挥重要作用，snRNPs是pre- mrna剪接的关键成分。尽管SMN复合物具有复杂的磷酸化模式，但人们对其翻译后修饰对其活性的调节知之甚少。几种磷酸酶参与了SMN的调控，包括核磷酸酶PPM1G和PP1 γ。在这里，我们系统地筛选了在SMN复合体中起调节作用的所有人类磷酸酶基因产物。我们使用完整增殖细胞Cajal小体中SMN的积累作为未受干扰的SMN复合物功能的读数，这些细胞积极组装snRNPs。29种蛋白磷酸酶的敲低干扰了Cajal体内SMN的积累，表明SMN复合物功能受损，其中包括催化活性不高的非受体型酪氨酸磷酸酶PTPN23/HD-PTP。PTPN23的敲低也导致SMN磷酸化模式的改变，但不影响SMN复合物的组装。我们进一步证明了SMN和PTPN23之间的相互作用，并证明PTPN23像SMN一样在细胞核和细胞质之间穿梭。我们的数据首次提供了SMN复合物调控因子的全面筛选，并建立了PTPN23在维持SMN高度磷酸化状态方面的新调控功能，这对于其在snRNP组装中的正常功能至关重要。
The survival motor neuron (SMN) complex fulfils essential functions in the assembly of snRNPs, which are key components in the splicing of pre-mRNAs. Little is known about the regulation of SMN complex activity by posttranslational modification despite its complicated phosphorylation pattern. Several phosphatases had been implicated in the regulation of SMN, including the nuclear phosphatases PPM1G and PP1 gamma. Here we systematically screened all human phosphatase gene products for a regulatory role in the SMN complex. We used the accumulation of SMN in Cajal bodies of intact proliferating cells, which actively assemble snRNPs, as a readout for unperturbed SMN complex function. Knockdown of 29 protein phosphatases interfered with SMN accumulation in Cajal bodies, suggesting impaired SMN complex function, among those the catalytically inactive, non-receptor-type tyrosine phosphatase PTPN23/HD-PTP. Knockdown of PTPN23 also led to changes in the phosphorylation pattern of SMN without affecting the assembly of the SMN complex. We further show interaction between SMN and PTPN23 and document that PTPN23, like SMN, shuttles between nucleus and cytoplasm. Our data provide the first comprehensive screen for SMN complex regulators and establish a novel regulatory function of PTPN23 in maintaining a highly phosphorylated state of SMN, which is important for its proper function in snRNP assembly.