Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Division for Development of Autophagy Modulating Drugs, Juntendo University Faculty of Medicine, Tokyo, Japan.
EMBO J. 2022 Nov 17;41(22):e111476. doi: 10.15252/embj.2022111476. Epub 2022 Oct 11.
Retrograde transport of lysosomes is recognised as a critical autophagy regulator. Here, we found that acrolein, an aldehyde that is significantly elevated in Parkinson's disease patient serum, enhances autophagy by promoting lysosomal clustering around the microtubule organising centre via a newly identified JIP4-TRPML1-ALG2 pathway. Phosphorylation of JIP4 at T217 by CaMK2G in response to Ca fluxes tightly regulated this system. Increased vulnerability of JIP4 KO cells to acrolein indicated that lysosomal clustering and subsequent autophagy activation served as defence mechanisms against cytotoxicity of acrolein itself. Furthermore, the JIP4-TRPML1-ALG2 pathway was also activated by H O , indicating that this system acts as a broad mechanism of the oxidative stress response. Conversely, starvation-induced lysosomal retrograde transport involved both the TMEM55B-JIP4 and TRPML1-ALG2 pathways in the absence of the JIP4 phosphorylation. Therefore, the phosphorylation status of JIP4 acts as a switch that controls the signalling pathways of lysosoma l distribution depending on the type of autophagy-inducing signal.
溶酶体逆行转运被认为是关键的自噬调控因子。在这里，我们发现丙烯醛（帕金森病患者血清中显著升高的醛）通过新发现的 JIP4-TRPML1-ALG2 途径促进溶酶体聚集在微管组织中心，从而增强自噬。CaMK2G 响应 Ca 流对 JIP4 的 T217 进行磷酸化，从而紧密调节该系统。JIP4 KO 细胞对丙烯醛的敏感性增加表明，溶酶体聚集和随后的自噬激活是对抗丙烯醛自身细胞毒性的防御机制。此外，H O 还激活了 JIP4-TRPML1-ALG2 途径，表明该系统是氧化应激反应的广泛机制。相反，饥饿诱导的溶酶体逆行转运涉及 TMEM55B-JIP4 和 TRPML1-ALG2 途径，而 JIP4 磷酸化缺失。因此，JIP4 的磷酸化状态充当一个开关，根据自噬诱导信号的类型控制溶酶体分布的信号通路。
