Xu Linlin, Lyu Xinxing, Wang Yibo, Ni Li, Li Pin, Zeng Piao, Wang Qixia, Chang Yunhao, Pan Chenglong, Hu Qingxia, Huang Shuhong, Dang Ningning
Department of Dermatology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China.
Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China.
Proc Natl Acad Sci U S A. 2025 Apr 15;122(15):e2411429122. doi: 10.1073/pnas.2411429122. Epub 2025 Apr 10.
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 knockout () 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.
包括LC3B（微管相关蛋白1轻链3β）在内的自噬相关8（Atg8）家族蛋白，在自噬过程的关键步骤中起关键作用。LC3B稳态的适当调节对其功能至关重要。尽管LC3B受到各种翻译后修饰（PTM）的调节，但其对LC3B蛋白质稳态的影响仍不清楚。Neddylation是一种最近发现的类泛素修饰，具有多种生物学作用。在这里，我们确定LC3B是Neddylation的一个特定靶点。这种修饰减弱了LC3B与泛素E3连接酶VHL和BIRC6的相互作用，从而减少了LC3B的泛素化。泛素缀合酶E2M（UBE2M）是Neddylation途径中的主要E2酶，其缺失会使LC3B不稳定并抑制自噬活性。杂合敲除（）小鼠表现出明显的衰老样表型，皮肤组织中LC3B表达降低且自噬受损。我们的研究结果表明，LC3B的Neddylation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一条潜在的治疗途径。
