Basolateral sorting signals regulating tissue-specific polarity of heteromeric monocarboxylate transporters in epithelia.
Basolateral sorting signals regulating tissue-specific polarity of heteromeric monocarboxylate transporters in epithelia.
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DOI：
10.1111/j.1600-0854.2010.01155.x
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Philp NJ
中科院分区：
文献类型：
--
作者：
Castorino JJ;Deborde S;Deora A;Schreiner R;Gallagher-Colombo SM;Rodriguez-Boulan E;Philp NJ
许多溶质转运体是由非糖基化催化亚基和糖基化附属亚基组成的异源二聚体。这些转运蛋白特异地极化到上皮的顶端或基底外膜，但这种极性可能会发生变化，以实现组织特异性功能。迄今为止，调节异质转运体的组织特异性极性的机制在很大程度上仍然未知。在这里，我们研究了决定质子偶联单羧酸转运体（MCT）家族的三个成员——MCT1、MCT3和MCT4及其附属亚基CD147的极性的分选信号。我们发现MCT3和MCT4在它们的c端细胞质尾部携带强烈的冗余基底外侧分选信号（BLSS），可以将带有顶端标记p75的融合蛋白引导到基底外侧膜。相比之下，MCT1缺乏BLSS，其极性由CD147决定，CD147含有一个弱的BLSS，可以引导Tac，但不能引导p75到达基底外侧膜。MDCK细胞的敲低实验表明，mct的基底侧分选依赖于网格蛋白，而不依赖于网格蛋白接头ap1b。我们的研究结果解释了MCT3和MCT4在基底外侧的一致定位以及MCT1在不同上皮中的可变定位。他们为异二聚体转运体的分类引入了一种新的范式，在这种范式中，催化和/或辅助亚基中的顶端和基底侧分类信号等级调节其组织特异性极性。
Many solute transporters are heterodimers comprised of non-glycosylated catalytic and glycosylated accessory subunits. These transporters are specifically polarized to the apical or basolateral membranes of epithelia but this polarity may vary to fulfill tissue-specific functions. To date, the mechanisms regulating the tissue-specific polarity of heteromeric transporters remain largely unknown. Here, we investigated the sorting signals that determine the polarity of three members of the proton-coupled monocarboxylate transporter (MCT) family, MCT1, MCT3 and MCT4, and their accessory subunit CD147. We show that MCT3 and MCT4 harbor strong redundant basolateral sorting signals (BLSS) in their C-terminal cytoplasmic tails that can direct fusion proteins with the apical marker p75 to the basolateral membrane. In contrast, MCT1 lacks a BLSS and its polarity is dictated by CD147, which contains a weak BLSS that can direct Tac, but not p75 to the basolateral membrane. Knockdown experiments in MDCK cells indicated that basolateral sorting of MCTs was clathrin-dependent but clathrin adaptor AP1B-independent. Our results explain the consistently basolateral localization of MCT3 and MCT4 and the variable localization of MCT1 in different epithelia. They introduce a new paradigm for the sorting of heterodimeric transporters in which a hierarchy of apical and basolateral sorting signals in the catalytic and/or accessory subunits regulates their tissue-specific polarity.
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影响因子：
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作者：
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