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非自噬性高尔基体-LC3 脂质化有助于 TFE3 应对高尔基体功能障碍的应激反应。

Non-autophagic Golgi-LC3 lipidation facilitates TFE3 stress response against Golgi dysfunction.

机构信息

School of biological sciences, Seoul National University, Seoul, 08826, Korea.

Interdisciplinary Program in Neuroscience, Seoul National University, Seoul, 08826, Korea.

出版信息

EMBO J. 2024 Nov;43(21):5085-5113. doi: 10.1038/s44318-024-00233-y. Epub 2024 Sep 16.

DOI:10.1038/s44318-024-00233-y
PMID:39284911
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11535212/
Abstract

Lipidated ATG8/LC3 proteins are recruited to single membrane compartments as well as autophagosomes, supporting their functions. Although recent studies have shown that Golgi-LC3 lipidation follows Golgi damage, its molecular mechanism and function under Golgi stress remain unknown. Here, by combining DLK1 overexpression as a new strategy for induction of Golgi-specific LC3 lipidation, and the application of Golgi-damaging reagents, we unravel the mechanism and role of Golgi-LC3 lipidation. Upon DLK1 overexpression, LC3 is lipidated on the Golgi apparatus in an ATG12-ATG5-ATG16L1 complex-dependent manner; a post-Golgi trafficking blockade is the primary cause of this lipidation. During Golgi stress, ATG16L1 is recruited through its interaction with V-ATPase for Golgi-LC3 lipidation. After post-Golgi trafficking inhibition, TFE3, a key regulator of the Golgi stress response, is translocated to the nucleus. Defects in LC3 lipidation disrupt this translocation, leading to an attenuation of the Golgi stress response. Together, our results reveal the mechanism and unexplored function of Golgi-LC3 lipidation in the Golgi stress response.

摘要

脂化的 ATG8/LC3 蛋白被招募到单一膜隔间和自噬体上，支持它们的功能。尽管最近的研究表明，高尔基体内 LC3 的脂质化紧随高尔基体损伤，但高尔基体应激下其分子机制和功能仍不清楚。在这里，我们通过结合过表达 DLK1 作为诱导高尔基体特异性 LC3 脂质化的新策略，以及应用高尔基体损伤试剂，揭示了高尔基体 LC3 脂质化的机制和作用。在 DLK1 过表达时，LC3 以 ATG12-ATG5-ATG16L1 复合物依赖性方式在高尔基器上发生脂化；高尔基体内质网转运受阻是这种脂化的主要原因。在高尔基体应激时，ATG16L1 通过与 V-ATPase 的相互作用被募集到高尔基体上进行 LC3 脂化。高尔基体内质网转运抑制后，高尔基体应激反应的关键调节因子 TFE3 易位到核内。LC3 脂化缺陷破坏了这种易位，导致高尔基体应激反应减弱。总之，我们的结果揭示了高尔基体 LC3 脂质化在高尔基体应激反应中的机制和未被探索的功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/4afcd38b7d9a/44318_2024_233_Fig11_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/4afcd38b7d9a/44318_2024_233_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/90bc18e23820/44318_2024_233_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/9fae4a84d679/44318_2024_233_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/4470b1ff6ded/44318_2024_233_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/3a6c0faa4b15/44318_2024_233_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/c28924b593d5/44318_2024_233_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/c87d7acea505/44318_2024_233_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/724ba7be37ce/44318_2024_233_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/671e76604835/44318_2024_233_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/49fadf542afd/44318_2024_233_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08b3/11535212/4afcd38b7d9a/44318_2024_233_Fig11_ESM.jpg

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