FIP200 控制 SQSTM1/p62 阳性液滴中 TBK1 的激活阈值。
FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates.
机构信息
Institute of Molecular Medicine I, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstr. 1, Building 22.03, 40225, Düsseldorf, Germany.
Department of Otorhinolaryngology and Head/Neck Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.
出版信息
Sci Rep. 2021 Jul 5;11(1):13863. doi: 10.1038/s41598-021-92408-4.
The protein kinase TBK1 is a central regulator of innate immune responses and autophagy, and ablation of either function has been linked to neuroinflammatory or degenerative diseases. Autophagy is an intracellular process that recycles old or damaged proteins and organelles. In recent years, the TBK1-dependent regulation of autophagy pathways has been characterized. However, the autophagy-dependent regulation of TBK1 activity awaits further clarification. Here, we observed that TBK1 is recruited to SQSTM1/p62-containing aggregates via the selective autophagy receptor TAX1BP1. In these aggregates, TBK1 phosphorylates SQSTM1/p62 at serine 403 and thus presumably regulates the efficient engulfment and clearance of these structures. We found that TBK1 activation is strongly increased if FIP200, a component of the autophagy-inducing ULK1 complex, is not present or cannot bind to TAX1BP1. Given our collective findings, we hypothesize that FIP200 ensures the inducible activation of TBK1 at SQSTM1/p62 condensates.
蛋白激酶 TBK1 是先天免疫反应和自噬的核心调节剂，其功能缺失与神经炎症或退行性疾病有关。自噬是一种回收旧的或受损蛋白质和细胞器的细胞内过程。近年来，TBK1 依赖的自噬途径的调节已被描述。然而，TBK1 活性的自噬依赖性调节仍有待进一步阐明。在这里，我们观察到 TBK1 通过选择性自噬受体 TAX1BP1 被募集到含有 SQSTM1/p62 的聚集体中。在这些聚集体中，TBK1 磷酸化 SQSTM1/p62 的丝氨酸 403，因此推测其调节这些结构的有效吞噬和清除。我们发现，如果自噬诱导的 ULK1 复合物的组成部分 FIP200 不存在或不能与 TAX1BP1 结合，TBK1 的激活会大大增强。鉴于我们的集体发现，我们假设 FIP200 可确保 TBK1 在 SQSTM1/p62 凝聚物中的诱导激活。
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