Small GTPase ARF6 Regulates Endocytic Pathway Leading to Degradation of ATP-Binding Cassette Transporter A1.
Small GTPase ARF6 Regulates Endocytic Pathway Leading to Degradation of ATP-Binding Cassette Transporter A1.
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DOI：
10.1161/atvbaha.116.308418
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Sviridov D
中科院分区：
文献类型：
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作者：
Mukhamedova N;Hoang A;Cui HL;Carmichael I;Fu Y;Bukrinsky M;Sviridov D
ATP结合盒转运体A1（ABCA 1）是负责细胞胆固醇流出的主要蛋白。ABCA 1的功能和功能在转录和转录后都受到调节，ABCA 1的内吞作用是翻译后调节的重要因素。功能性ABCA 1位于质膜上，但可以被内化并降解或再循环回质膜。降解和再循环途径之间的相互作用决定了ABCA 1的丰度，并可能有助于细胞内胆固醇的流出。在这里，我们表明，负责ABCA 1的内化，导致其在巨噬细胞中的降解的主要途径是ARF6依赖性内吞途径。该途径在调节ABCA 1丰度和质膜胆固醇流出中占主导地位。相反，细胞内胆固醇的流出主要由ARF6独立途径控制，抑制ARF6使ABCA 1进入再循环内体，增强细胞内胆固醇的流出。我们的结论是，ARF6依赖性途径是负责ABCA 1的内化和降解的主要途径，而ARF6非依赖性内吞途径可能有助于ABCA 1的回收和细胞内胆固醇的流出。
ATP binding cassette transporter A1 (ABCA1) is the principal protein responsible for cellular cholesterol efflux. Abundance and functionality of ABCA1 is regulated both transcriptionally and post-translationally, with endocytosis of ABCA1 being an important element of post-translational regulation. Functional ABCA1 resides on the plasma membrane, but can be internalized and either degraded or recycled back to the plasma membrane. The interaction between the degradative and recycling pathways determines the abundance of ABCA1 and may contribute to the efflux of intracellular cholesterol. Here, we show that the principal pathway responsible for the internalization of ABCA1 leading to its degradation in macrophages is ARF6-dependent endocytic pathway. This pathway was predominant in regulation of ABCA1 abundance and efflux of plasma membrane cholesterol. Conversely, the efflux of intracellular cholesterol was predominantly controlled by ARF6-indepednent pathways, and inhibition of ARF6 shifted ABCA1 into recycling endosomes enhancing efflux of intracellular cholesterol. We conclude that ARF6-dependent pathway is the predominant route responsible for the ABCA1 internalization and degradation, while ARF6-independent endocytic pathways may contribute to ABCA1 recycling and efflux of intracellular cholesterol.