Neddylation modification stabilizes LC3B by antagonizing its ubiquitin-mediated degradation and promoting autophagy in skin

IF 9.1 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-04-10 DOI:10.1073/pnas.2411429122

Linlin Xu, Xinxing Lyu, Yibo Wang, Li Ni, Pin Li, Piao Zeng, Qixia Wang, Yunhao Chang, Chenglong Pan, Qingxia Hu, Shuhong Huang, Ningning Dang

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引用次数: 0

Abstract

The Atg8-family proteins, including LC3B (microtubule-associated protein 1 light chain 3 beta), are pivotal for key steps in the autophagy process. Proper regulation of LC3B homeostasis is essential for its function. Although LC3B is modulated by various posttranslational modifications (PTMs), the impact of these modifications on LC3B protein homeostasis remains unclear. Neddylation, a recently identified ubiquitin-like modification, plays diverse biological roles. Here, we identify LC3B as a specific target for neddylation. This modification weakens LC3B’s interaction with the ubiquitin E3 ligases VHL and BIRC6, thereby reducing LC3B ubiquitination. Depletion of ubiquitin-conjugating enzyme E2M (UBE2M), the primary E2 enzyme in the neddylation pathway, destabilizes LC3B and suppresses autophagy activity. Heterozygous Ube2m knockout ( Ube2m +/− ) mice exhibit pronounced aging-like phenotypes, with reduced LC3B expression and impaired autophagy in skin tissues. Our findings demonstrate that LC3B neddylation is vital for maintaining its stability and regulating autophagy flux, offering a potential therapeutic avenue to mitigate aging-related processes.

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泛素化修饰通过拮抗其泛素介导的降解和促进皮肤自噬来稳定LC3B

atg8家族蛋白，包括LC3B（微管相关蛋白1轻链3 β），在自噬过程的关键步骤中起关键作用。适当调节LC3B的内稳态对其功能的发挥至关重要。尽管LC3B受到各种翻译后修饰（PTMs）的调节，但这些修饰对LC3B蛋白稳态的影响尚不清楚。类泛素化修饰是最近发现的一种类泛素修饰，具有多种生物学作用。在这里，我们确定LC3B是类化修饰的特定靶点。这种修饰减弱了LC3B与泛素E3连接酶VHL和BIRC6的相互作用，从而降低了LC3B的泛素化。泛素偶联酶E2M （UBE2M）是类化化途径中的主要E2酶，它的缺失会破坏LC3B的稳定性，抑制自噬活性。杂合子Ube2m敲除（Ube2m +/−）小鼠表现出明显的衰老样表型，LC3B表达降低，皮肤组织自噬受损。我们的研究结果表明，LC3B类化修饰对于维持其稳定性和调节自噬通量至关重要，为减轻衰老相关过程提供了潜在的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.