The intraflagellar transport protein IFT20 controls lysosome biogenesis by regulating the post-Golgi transport of acid hydrolases
The intraflagellar transport protein IFT20 controls lysosome biogenesis by regulating the post-Golgi transport of acid hydrolases
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DOI：
10.1038/s41418-019-0357-y
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发表时间：
2020-01-01
影响因子：
12.4
通讯作者：
Baldari, Cosima T.
中科院分区：
文献类型：
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作者：
Finetti, Francesca;Cassioli, Chiara;Baldari, Cosima T.
初级纤毛的组装和功能依赖于多分子鞭毛内转运(IFT)复合体，这些复合体通过与分子马达的相互作用沿着轴丝微管运送货物。此外，IFT系统最近还被认为与自噬和纤毛发生之间的相互作用有关。我们以前已经报道过IFT20和IFT复合体的其他成分参与了非纤毛T细胞中免疫突触的组装，这表明在纤毛细胞中受IFT系统调控的其他细胞过程，包括自噬，可能被缺乏纤毛的细胞所共享。从观察到IFT20缺乏的T细胞自噬清除缺陷和脂滴积累开始，我们证明IFT20是溶酶体发生和功能所必需的，通过控制酸性水解酶的溶酶体靶向。这一功能涉及其调节阳离子非依赖性甘露糖-6-磷酸受体(CI-MPR)到跨高尔基体网络的逆行交通的能力，这是通过将循环CI-MPR偶联到微管运动动力蛋白来实现的。与溶酶体缺陷一致，在IFT20缺陷的细胞中可以观察到依赖TFLB的溶酶体基因网络的表达上调，这与紧张性T细胞抗原受体信号转导和mTOR活性缺陷有关。我们还发现，IFT20的溶酶体相关功能延伸到T细胞以外的非纤毛细胞，以及纤毛细胞。我们的发现提供了第一个证据，表明控制纤毛发生的IFT系统的一个组件与溶酶体的生物发生有关。
The assembly and function of the primary cilium depends on multimolecular intraflagellar transport (IFT) complexes that shuttle their cargo along the axonemal microtubules through their interaction with molecular motors. The IFT system has been moreover recently implicated in a reciprocal interplay between autophagy and ciliogenesis. We have previously reported that IFT20 and other components of the IFT complexes participate in the assembly of the immune synapse in the non-ciliated T cell, suggesting that other cellular processes regulated by the IFT system in ciliated cells, including autophagy, may be shared by cells lacking a cilium. Starting from the observation of a defect in autophagic clearance and an accumulation of lipid droplets in IFT20-deficient T cells, we show that IFT20 is required for lysosome biogenesis and function by controlling the lysosomal targeting of acid hydrolases. This function involves its ability to regulate the retrograde traffic of the cation-independent mannose-6-phosphate receptor (CI-MPR) to the trans-Golgi network, which is achieved by coupling recycling CI-MPRs to the microtubule motor dynein. Consistent with the lysosomal defect, an upregulation of the TFLB-dependent expression of the lysosomal gene network can be observed in IFT20-deficient cells, which is associated with defective tonic T-cell antigen receptor signaling and mTOR activity. We additionally show that the lysosome-related function of IFT20 extends to non-ciliated cells other than T cells, as well as to ciliated cells. Our findings provide the first evidence that a component of the IFT system that controls ciliogenesis is implicated in the biogenesis of lysosomes.