A Tecpr1-Dependent Selective Autophagy Pathway Targets Bacterial Pathogens
A Tecpr1-Dependent Selective Autophagy Pathway Targets Bacterial Pathogens
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DOI：
10.1016/j.chom.2011.04.010
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发表时间：
2011-05-19
影响因子：
30.3
通讯作者：
Sasakawa, Chihiro
中科院分区：
文献类型：
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作者：
Ogawa, Michinaga;yoshikawa, Yuko;Sasakawa, Chihiro
细菌病原体的选择性自噬是宿主的一种先天免疫机制。选择性自噬的特征是以不同的货物受体为基础的，但不同的货物受体作为自噬降解靶点的机制尚不清楚。在这项研究中，我们发现了一个高度保守的Tectonin结构域蛋白Tecpr1，它是ATG5的结合伙伴，与ATG5共定位于含志贺氏菌的噬菌体。Tecpr1活性是有效的自噬靶向细菌所必需的，但对雷帕霉素或饥饿诱导的典型自噬没有影响。Tecpr1与Wipi-2相互作用，Wipi-2是酵母Atg18同源物，PI(3)P-相互作用蛋白是形成噬菌体所必需的，它们共同定位于噬菌体。尽管Tecpr1基因缺陷的小鼠看起来是正常的，但Tecpr1基因缺陷的MEF在选择性自噬方面存在缺陷，并支持志贺氏菌细胞内增殖增加。此外，在Tecpr1基因敲除的MEF中，线粒体去极化和错误折叠的蛋白质聚集体积累。因此，我们确定了一条依赖Tecpr1的途径在选择性自噬的靶向细菌病原体方面非常重要。
Selective autophagy of bacterial pathogens represents a host innate immune mechanism. Selective autophagy has been characterized on the basis of distinct cargo receptors but the mechanisms by which different cargo receptors are targeted for autophagic degradation remain unclear. In this study we identified a highly conserved Tectonin domain-containing protein, Tecpr1, as an Atg5 binding partner that colocalized with Atg5 at Shigella-containing phagophores. Tecpr1 activity is necessary for efficient autophagic targeting of bacteria, but has no effect on rapamycin- or starvation-induced canonical autophagy. Tecpr1 interacts with WIPI-2, a yeast Atg18 homolog and PI(3)P-interacting protein required for phagophore formation, and they colocalize to phagophores. Although Tecpr1-deficient mice appear normal, Tecpr1-deficient MEFs were defective for selective autophagy and supported increased intracellular multiplication of Shigella. Further, depolarized mitochondria and misfolded protein aggregates accumulated in the Tecpr1-knockout MEFs. Thus, we identify a Tecpr1-dependent pathway as important in targeting bacterial pathogens for selective autophagy.