Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
Nat Cell Biol. 2024 Sep;26(9):1558-1570. doi: 10.1038/s41556-024-01481-0. Epub 2024 Aug 22.
Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality.
细胞通过多泡体以胞外体的形式释放胞腔内囊泡来与其他细胞进行通讯。尽管最近的研究表明胞外体生物发生和自噬之间存在密切联系，但详细的机制尚不完全清楚。在这里，我们采用了综合的 RNA 干扰筛选自噬相关因子，并发现自噬的负调控因子 Rubicon 对于胞外体的释放是必不可少的。Rubicon 将 WIPI2d 招募到内体以促进胞外体的生物发生。WIPI2d 的相互作用组分析鉴定了形成腔内囊泡所必需的 ESCRT 成分。值得注意的是，我们发现 Rubicon 对于小鼠中与年龄相关的胞外体释放增加是必需的。此外，血清胞外体的小 RNA 测序显示，Rubicon 决定了与细胞衰老和长寿途径相关的胞外体 microRNA 的命运。总之，我们目前的结果表明，Rubicon-WIPI 轴作为胞外体生物发生的关键调节剂，负责与年龄相关的胞外体数量和质量变化。
