Nuclear RNA transcript levels modulate nucleocytoplasmic distribution of ALS/FTD-associated protein FUS.
Nuclear RNA transcript levels modulate nucleocytoplasmic distribution of ALS/FTD-associated protein FUS.
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DOI：
10.1038/s41598-022-12098-4
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发表时间：
2022-05-17
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
FUS是一种核内RNA/DNA结合蛋白，在神经退行性疾病ALS和FTD中错误定位于细胞质。尽管存在导致核进口缺陷的FUS致病突变，但ALS/FTD患者中的一部分显示出野生型FUS的细胞质积累，尽管其潜在机制尚不清楚。在这里，我们证实转录抑制，特别是RNA聚合酶II(RNAP II)，诱导FUS细胞质易位，但我们表明，其他几个胁迫不会。我们意外地发现，不同FUS抗体的表位特异性显著影响免疫荧光测定的表观FUS核质比，这解释了先前研究中不一致的观察结果。值得注意的是，即使在转录被抑制的情况下，核mRNA输出因子Nxf1或RNA外体辅助因子MTR4的缺失也促进了FUS核保留，而错位与核蛋白输出因子CRM1和输入因子TNPO1无关。最后，我们报告了散发性ALS iPS细胞中新生RNAP II转录本的水平降低，包括那些已知与FUS结合的转录本，这可能与异常转录控制和FUS细胞质错误定位有关。因此，我们的发现揭示了影响核RNAP II转录本积累的因素调节了FUS核浆的动态平衡，并提供了证据表明RNAP II转录减少可能导致FUS在ALS细胞质中的错误定位。
Fused in Sarcoma (FUS) is a nuclear RNA/DNA binding protein that mislocalizes to the cytoplasm in the neurodegenerative diseases ALS and FTD. Despite the existence of FUS pathogenic mutations that result in nuclear import defects, a subset of ALS/FTD patients display cytoplasmic accumulation of wild-type FUS, although the underlying mechanism is unclear. Here we confirm that transcriptional inhibition, specifically of RNA polymerase II (RNAP II), induces FUS cytoplasmic translocation, but we show that several other stresses do not. We found unexpectedly that the epitope specificity of different FUS antibodies significantly affects the apparent FUS nucleocytoplasmic ratio as determined by immunofluorescence, explaining inconsistent observations in previous studies. Significantly, depletion of the nuclear mRNA export factor NXF1 or RNA exosome cofactor MTR4 promotes FUS nuclear retention, even when transcription is repressed, while mislocalization was independent of the nuclear protein export factor CRM1 and import factor TNPO1. Finally, we report that levels of nascent RNAP II transcripts, including those known to bind FUS, are reduced in sporadic ALS iPS cells, linking possible aberrant transcriptional control and FUS cytoplasmic mislocalization. Our findings thus reveal that factors that influence accumulation of nuclear RNAP II transcripts modulate FUS nucleocytoplasmic homeostasis, and provide evidence that reduced RNAP II transcription can contribute to FUS mislocalization to the cytoplasm in ALS.
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影响因子：
10.5
作者：
Müller-McNicoll M;Botti V;de Jesus Domingues AM;Brandl H;Schwich OD;Steiner MC;Curk T;Poser I;Zarnack K;Neugebauer KM
通讯作者：
Neugebauer KM
影响因子：
12.7
作者：
Mitchell JC;McGoldrick P;Vance C;Hortobagyi T;Sreedharan J;Rogelj B;Tudor EL;Smith BN;Klasen C;Miller CC;Cooper JD;Greensmith L;Shaw CE
通讯作者：
Shaw CE
影响因子：
7.4
作者：
D'Amico, Emanuele;Factor-Litvak, Pam;Santella, Regina M.;Mitsumoto, Hiroshi
通讯作者：
Mitsumoto, Hiroshi
影响因子：
6
作者：
Kretov, Dmitry A.;Mordovkina, Daria A.;Ovchinnikov, Lev P.
通讯作者：
Ovchinnikov, Lev P.
影响因子：
4.5
作者：
Nakaya, Tadashi;Alexiou, Panagiotis;Mourelatos, Zissimos
通讯作者：
Mourelatos, Zissimos