Rab11在内体-溶酶体途径的体内平衡中的作用。,Experimental Cell Research - X-MOL

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Rab11在内体-溶酶体途径的体内平衡中的作用。
Experimental Cell Research ( IF 3.3 ) Pub Date : 2019-04-11 , DOI: 10.1016/j.yexcr.2019.04.010
Khalisah L Zulkefli ₁ , Fiona J Houghton ₁ , Prajakta Gosavi ₁ , Paul A Gleeson ₁

Affiliation

较小的GTPases Rab11a和11b是膜运输的关键调节因子，仅位于回收的内体和早期内体中。Rab11在回收途径中的功能已得到很好的定义，但是，Rab11在早期内体中的作用仍然很差。在这里，我们使用CRISPR / Cas9生成了不含Rab11a或Rab11b的HeLa细胞系，以功能方式剖析了这两个Rab11家族成员在回收和内体溶酶体系统中的作用。Rab11a和Rab11b都对回收内体产生的输卵管动力学做出了贡献，而Rab11a在转铁蛋白受体的回收中起主要作用。Rab11a或Rab11b的删除导致早期内体的扩大和内体-溶酶体途径的扰动。惊人地 Rab11a敲除细胞显示功能性晚期内体/溶酶体以及溶酶追踪阳性细胞器的密度增加，后者主要集中在核周位置，表明内体/溶酶体途径的稳态已受到干扰。此外，在Rab11a敲除细胞中，晚期内体与TGN之间的非阳离子依赖性甘露糖6-磷酸受体（CI-M6PR）的细胞内再循环存在功能缺陷，即与CI-M6PR降解增强相关的缺陷。Rab11a基因敲除细胞中野生型Rab11a的表达挽救了晚期内体/溶酶体表型。总体而言，这些结果表明，Rab11a和Rab11b具有重叠且截然不同的功能，而Rab11a出乎意料地在内体-溶酶体生物发生的体内平衡中起着核心作用。

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A role for Rab11 in the homeostasis of the endosome-lysosomal pathway.

The small GTPases Rab11a and 11b are key regulators of membrane transport, localised to the recycling endosomes and also early endosomes. The function of Rab11 within the recycling pathway has been well defined, however, the role of Rab11 at the early endosomes remains poorly characterised. Here, we have generated HeLa cell lines devoid of either Rab11a or Rab11b using CRISPR/Cas9 to functionally dissect the roles of these two Rab11 family members in recycling and in the endosomal-lysosomal system. Both Rab11a and Rab11b contribute to the dynamics of tubulation arising from recycling endosomes whereas Rab11a has the major role in recycling of transferrin receptor. Deletion of either Rab11a or Rab11b resulted in the formation of enlarged early endosomes and perturbation of the endosomal-lysosomal pathway. Strikingly, Rab11a knock-out cells showed an increased density of functional late endosomes/lysosomes as well as lysotracker-positive organelles which were primarily concentrated in a perinuclear location, indicating that the homeostasis of the endosome/lysosome pathway had been perturbed. Moreover, in Rab11a knockout cells there was a functional defect in the intracellular recycling of the cation-independent mannose 6-phosphate receptor (CI-M6PR) between the late endosomes and the TGN, a defect associated with enhanced degradation of CI-M6PR. Expression of wild-type Rab11a in Rab11a knockout cells rescued the late endosome/lysosome phenotype. Overall, these results indicate that Rab11a and Rab11b have overlapping and distinct functions and that Rab11a, unexpectedly, plays a central role in the homeostasis of endosomal-lysosomal biogenesis.

更新日期：2019-04-12

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