Neddylation modification stabilizes LC3B by antagonizing its ubiquitin- mediated degradation and promoting autophagy in skin
成果类型：
Article
署名作者：
Xu, Linlin; Lyu, Xinxing; Wang, Yibo; Ni, Li; Li, Pin; Zeng, Piao; Wang, Qixia; Chang, Yunhao; Pan, Chenglong; Hu, Qingxia; Huang, Shuhong; Dang, Ningning
署名单位：
Shandong First Medical University & Shandong Academy of Medical Sciences; Shandong University; Shandong First Medical University & Shandong Academy of Medical Sciences; Shandong First Medical University & Shandong Academy of Medical Sciences; Shandong First Medical University & Shandong Academy of Medical Sciences; Nanjing Medical University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-11743
DOI：
10.1073/pnas.2411429122
发表日期：
2025-04-15
关键词：
nedd8-activating enzyme
hippo kinases
resistance
inhibitor
摘要：
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 post-translational 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.