FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination.
FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination.
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DOI：
10.1083/jcb.201608022
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发表时间：
2017-04-03
期刊：
影响因子：
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通讯作者：
Mili S
中科院分区：
文献类型：
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作者：
Yasuda K;Clatterbuck-Soper SF;Jackrel ME;Shorter J;Mili S
肌萎缩性侧索硬化症相关突变促进细胞质FUS包涵体的形成。在这项研究中，Yasuda等人发现，在成纤维细胞和神经元中，激酶1被隔离在FUS包裹体中，导致去酪化微管的丢失和特异性rna的错定位。肉瘤中融合的rna结合蛋白（FUS）的细胞质包涵体代表一种无膜核糖核蛋白室。肌萎缩性侧索硬化症（ALS）相关突变可促进FUS包涵体的形成，但影响包涵体形成的细胞功能尚不明确。在这项研究中，我们发现FUS包涵体导致成纤维细胞突起和神经元轴突特异性rna的错误定位。这是由FUS内含物中激酶1 mRNA和蛋白的募集介导的，导致去酪氨酸谷氨酸(Glu) -微管（MTs; Glu-MTs）的丢失，并且无法支持rna在突起处的定位。重要的是，使用工程Hsp104分解气体溶解FUS包涵体，或过度表达激酶-1，可以逆转这些影响。我们进一步提供的证据表明，激酶1影响MT去酪氨酸不是通过改变MT的稳定性，而是通过靶向微管蛋白羧肽酶到特定MT上。有趣的是，其他病理内含物也会导致类似的结果，但通过明显不同的机制。这些结果揭示了一种新的激酶依赖机制控制MT细胞骨架，并确定了glu -MT丢失和RNA错定位是ALS致病性突变的常见结果。
Amyotrophic lateral sclerosis–associated mutations promote the formation of cytoplasmic FUS inclusions. In this study, Yasuda et al. show in fibroblasts and neurons that kinesin-1 is sequestered in FUS inclusions, resulting in a loss of detyrosinated microtubules and mislocalization of specific RNAs. Cytoplasmic inclusions of the RNA-binding protein fused in sarcoma (FUS) represent one type of membraneless ribonucleoprotein compartment. Formation of FUS inclusions is promoted by amyotrophic lateral sclerosis (ALS)–linked mutations, but the cellular functions affected upon inclusion formation are poorly defined. In this study, we find that FUS inclusions lead to the mislocalization of specific RNAs from fibroblast cell protrusions and neuronal axons. This is mediated by recruitment of kinesin-1 mRNA and protein within FUS inclusions, leading to a loss of detyrosinated glutamate (Glu)–microtubules (MTs; Glu-MTs) and an inability to support the localization of RNAs at protrusions. Importantly, dissolution of FUS inclusions using engineered Hsp104 disaggregases, or overexpression of kinesin-1, reverses these effects. We further provide evidence that kinesin-1 affects MT detyrosination not through changes in MT stability, but rather through targeting the tubulin carboxypeptidase enzyme onto specific MTs. Interestingly, other pathological inclusions lead to similar outcomes, but through apparently distinct mechanisms. These results reveal a novel kinesin-dependent mechanism controlling the MT cytoskeleton and identify loss of Glu-MTs and RNA mislocalization as common outcomes of ALS pathogenic mutations.