Annexin A1 Tethers Membrane Contact Sites that Mediate ER to Endosome Cholesterol Transport.
Annexin A1 Tethers Membrane Contact Sites that Mediate ER to Endosome Cholesterol Transport.
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DOI：
10.1016/j.devcel.2016.05.005
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发表时间：
2016-06-06
影响因子：
11.8
通讯作者：
Futter CE
中科院分区：
文献类型：
--
作者：
Eden ER;Sanchez-Heras E;Tsapara A;Sobota A;Levine TP;Futter CE
ER和多泡内体/体（MVB）之间的膜接触位点在内体定位和分裂以及神经突生长中起重要作用。ER-MVB接触还通过提供ER定位的磷酸酶PTP 1B与内吞的EGFR相互作用的位点在表皮生长因子受体（EGFR）酪氨酸激酶下调中起作用，然后受体被分选到管腔内囊泡（ILV）上。在这里，我们表明，这些接触是由膜联蛋白A1和它的钙依赖性配体，S100 A11，并形成一个亚群的差异调节的ER和内吞细胞器之间的接触位点。当内体中低密度脂蛋白胆固醇低时，膜联蛋白A1调节的接触在ER衍生的胆固醇转移到MVB中起作用。这种固醇运输依赖于ER定位的VAP和内体氧固醇结合蛋白ORP 1 L之间的相互作用，并且是MVB内ILV形成所需的，因此是EGFR信号传导的空间调节所需的。ER-内吞细胞器接触位点的多个生物化学上不同的群体膜联蛋白A1-S100 A11相互作用栓系ER与EGFR阳性内体的接触ER至内体胆固醇转移以支持ILV形成需要接触位点ER至内体胆固醇转运依赖于直接VAPA-ORP 1 L相互作用Eden et al.鉴定膜联蛋白A1作为ER膜接触位点与含EGFR内体的系链。在低胆固醇条件下，膜联蛋白A1调节的接触位点是ER衍生的胆固醇转运到内体所必需的。这对于在空间上调节EGFR信号传导的内体腔内形成腔内囊泡是必需的。
Membrane contact sites between the ER and multivesicular endosomes/bodies (MVBs) play important roles in endosome positioning and fission and in neurite outgrowth. ER-MVB contacts additionally function in epidermal growth factor receptor (EGFR) tyrosine kinase downregulation by providing sites where the ER-localized phosphatase, PTP1B, interacts with endocytosed EGFR before the receptor is sorted onto intraluminal vesicles (ILVs). Here we show that these contacts are tethered by annexin A1 and its Ca2+-dependent ligand, S100A11, and form a subpopulation of differentially regulated contact sites between the ER and endocytic organelles. Annexin A1-regulated contacts function in the transfer of ER-derived cholesterol to the MVB when low-density lipoprotein-cholesterol in endosomes is low. This sterol traffic depends on interaction between ER-localized VAP and endosomal oxysterol-binding protein ORP1L, and is required for the formation of ILVs within the MVB and thus for the spatial regulation of EGFR signaling. Multiple biochemically distinct populations of ER-endocytic organelle contact sites Annexin A1-S100A11 interaction tethers ER contacts with EGFR-positive endosomes ER-to-endosome cholesterol transfer to support ILV formation requires contact sites ER to endosome cholesterol transport depends on direct VAPA-ORP1L interaction Eden et al. identify annexin A1 as a tether for ER membrane contact sites with EGFR-containing endosomes. Under low cholesterol conditions, annexin A1-regulated contact sites are required for ER-derived cholesterol transport to endosomes. This is necessary for the formation of intraluminal vesicles within the endosomal lumen that spatially regulate EGFR signaling.