Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.
Elife. 2022 Apr 11;11:e74531. doi: 10.7554/eLife.74531.
Autophagy receptor (or adaptor) proteins facilitate lysosomal destruction of various organelles in response to cellular stress, including nutrient deprivation. To what extent membrane-resident autophagy receptors also respond to organelle-restricted cues to induce selective autophagy remains poorly understood. We find that latent activation of the yeast pexophagy receptor Atg36 by the casein kinase Hrr25 in rich media is repressed by the ATPase activity of Pex1/6, the catalytic subunits of the exportomer AAA+ transmembrane complex enabling protein import into peroxisomes. Quantitative proteomics of purified Pex3, an obligate Atg36 coreceptor, support a model in which the exportomer tail anchored to the peroxisome membrane represses Atg36 phosphorylation on Pex3 without assistance from additional membrane factors. Indeed, we reconstitute inhibition of Atg36 phosphorylation using soluble Pex1/6 and define an N-terminal unstructured region of Atg36 that enables regulation by binding to Pex1. Our findings uncover a mechanism by which a compartment-specific AAA+ complex mediating organelle biogenesis and protein quality control staves off induction of selective autophagy.
自噬受体（或衔接蛋白）在细胞应激（包括营养缺乏）时，促进溶酶体对各种细胞器的降解。膜驻留自噬受体在何种程度上也响应于细胞器特有的信号来诱导选择性自噬，目前仍知之甚少。我们发现，在富含营养的培养基中，酵母 pexophagy 受体 Atg36 被酪蛋白激酶 Hrr25 潜在激活，这种激活被输出体 AAA+跨膜复合物的催化亚基 Pex1/6 的 ATP 酶活性所抑制，该复合物使蛋白能够导入过氧化物酶体。对必需的 Atg36 核心受体 Pex3 进行的定量蛋白质组学研究支持这样一种模型，即输出体尾部锚定在过氧化物酶体膜上，在没有其他膜因子辅助的情况下抑制 Pex3 上 Atg36 的磷酸化。事实上，我们使用可溶性 Pex1/6 重新构建了 Atg36 磷酸化的抑制作用，并定义了 Atg36 的一个 N 端无结构区域，该区域能够通过与 Pex1 结合来进行调节。我们的研究结果揭示了一种机制，即一种特定于隔室的 AAA+ 复合物，通过介导细胞器生物发生和蛋白质量控制，来阻止选择性自噬的诱导。
