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ALG-2 activates the MVB sorting function of ALIX through relieving its intramolecular interaction

机译：ALG-2通过减轻其分子内相互作用来激活ALIX的MVB分选功能

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The modular adaptor protein ALIX is critically involved in endosomal sorting complexes required for transport (ESCRT)-mediated multivesicular body (MVB) sorting of activated epidermal growth factor receptor (EGFR); however, ALIX contains a default intramolecular interaction that renders ALIX unable to perform this ESCRT function. The ALIX partner protein ALG-2 is a calcium-binding protein that belongs to the calmodulin superfamily. Prompted by a defined biological function of calmodulin, we determined the role of ALG-2 in regulating ALIX involvement in MVB sorting of activated EGFR. Our results show that calcium-dependent ALG-2 interaction with ALIX completely relieves the intramolecular interaction of ALIX and promotes CHMP4-dependent ALIX association with the membrane. EGFR activation induces increased ALG-2 interaction with ALIX, and this increased interaction is responsible for increased ALIX association with the membrane. Functionally, inhibition of ALIX activation by ALG-2 inhibits MVB sorting of activated EGFR as effectively as inhibition of ALIX interaction with CHMP4 does; however, inhibition of ALIX activation by ALG-2 does not affect cytokinetic abscission or equine infectious anemia virus (EIAV) budding. These findings indicate that calcium-dependent ALG-2 interaction with ALIX is specifically responsible for generating functional ALIX that supports MVB sorting of ubiquitinated membrane receptors.
机译：模块化衔接蛋白ALIX关键参与活化表皮生长因子受体（EGFR）的转运（ESCRT）介导的多囊体（MVB）分选所需的内体分选复合物;但是，ALIX包含默认的分子内相互作用，使ALIX无法执行此ESCRT功能。 ALIX伴侣蛋白ALG-2是一种钙结合蛋白，属于钙调蛋白超家族。由钙调蛋白的确定的生物学功能提示，我们确定了ALG-2在调节ALIX参与活化EGFR MVB分选中的作用。我们的结果表明，钙依赖的ALG-2与ALIX的相互作用完全缓解了ALIX的分子内相互作用，并促进了CHMP4依赖的ALIX与膜的缔合。 EGFR激活诱导了ALG-2与ALIX的相互作用增加，而这种相互作用的增加导致ALIX与膜的缔合增加。从功能上讲，ALG-2对ALIX激活的抑制作用与对ALIX与CHMP4的相互作用的抑制作用一样，对EGFR的MVB分选具有抑制作用。但是，ALG-2对ALIX激活的抑制作用不会影响细胞动力学的脱落或马传染性贫血病毒（EIAV）萌芽。这些发现表明，钙依赖性ALG-2与ALIX的相互作用特别负责产生功能性ALIX，该功能性ALIX支持泛素化膜受体的MVB分选。

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