Irs4p and Tax4p: Two redundant EH domain proteins involved in autophagy
Irs4p and Tax4p: Two redundant EH domain proteins involved in autophagy
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DOI：
10.1111/j.1600-0854.2008.00715.x
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发表时间：
2008-05-01
期刊：
影响因子：
4.5
通讯作者：
Galan, Jean-Marc
中科院分区：
文献类型：
--
作者：
Bugnicourt, Amandine;Mari, Muriel;Galan, Jean-Marc
携带EPS15同源性（EH）结构域的蛋白从酵母到哺乳动物都存在。该蛋白家族的特征成员都参与细胞内运输，典型的内吞作用和内吞循环。我们重点研究了该家族的两个成员——酿酒酵母Irs4p和Tax4p，它们的功能还没有被很好地描述。我们发现IRS4的缺失改变了邻近基因VPS51的功能，VPS51参与内吞循环。弥补vp51p缺失的irs4 Delta tax4 Delta细胞（irs4 Delta tax4 Delta*）在内吞作用和内体再循环方面没有缺陷，明显地将这两种EH蛋白与其他蛋白家族成员区分开来。由于Irs4p在诱导自噬时被磷酸化，因此我们研究了这两种蛋白在后一过程中的潜在作用。我们观察到饥饿后ir4 Delta tax4 Delta*细胞的生存能力丧失，因为大量自噬延迟。Irs4p和Tax4p也是食腐所必需的，但不是细胞质到液泡途径所必需的。在生长的细胞中，Irs4p和Tax4p定位于与核内体和高尔基区室不同的细胞质点。在诱导自噬的条件下，Irs4p和Tax4p部分定位于自噬体前结构（pre-autophagosomal structure， PAS），并且需要有效地招募到PAS Atg17p，这是一种调节自噬反应的因子。我们提出Irs4p和Tax4p是Atg17p上游自噬过程的两个冗余调节剂，可能在导致自噬机制在饥饿反应中激活的信号事件中。
Proteins carrying EPS15 homology (EH) domains are present from yeast to mammals. The characterized members of this protein family are all involved in intracellular trafficking, typically endocytosis and endocytic recycling. We focused on two members of this family in Saccharomyces cerevisiae Irs4p and Tax4p, whose functions are less well characterized. We show that the deletion of IRS4 altered the function of a neighboring gene, VPS51, involved in endocytic recycling. The irs4 Delta tax4 Delta cells complemented for the loss of Vps51p (irs4 Delta tax4 Delta*) display no defects in endocytosis and endosomal recycling, clearly differentiating these two EH proteins from the other protein family members. Because Irs4p is phosphorylated when autophagy is induced, we studied the potential role of these two proteins in this latter process. We observed a loss of viability upon starvation in irs4 Delta tax4 Delta* cells because of a delay in bulk autophagy. Irs4p and Tax4p are also required for pexophagy but not for the cytoplasm-to-vacuole pathway. In growing cells, Irs4p and Tax4p colocalized to few cytoplasmic puncta distinct from endosomes and Golgi compartments. In conditions inducing autophagy, Irs4p and Tax4p partially localized to the pre-autophagosomal structure (PAS) and are required to efficiently recruit to the PAS Atg17p, a factor modulating the autophagic response. We propose that Irs4p and Tax4p are two redundant modulators of the autophagic processes acting upstream from Atg17p, possibly in the signaling events leading to the activation of the autophagic machinery in response to starvation.