Kenific Candia M, Stehbens Samantha J, Goldsmith Juliet, Leidal Andrew M, Faure Nathalie, Ye Jordan, Wittmann Torsten, Debnath Jayanta
Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143.
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143.
J Cell Biol. 2016 Feb 29;212(5):577-90. doi: 10.1083/jcb.201503075. Epub 2016 Feb 22.
Autophagy is a catabolic pathway involving the sequestration of cellular contents into a double-membrane vesicle, the autophagosome. Although recent studies have demonstrated that autophagy supports cell migration, the underlying mechanisms remain unknown. Using live-cell imaging, we uncover that autophagy promotes optimal migratory rate and facilitates the dynamic assembly and disassembly of cell-matrix focal adhesions (FAs), which is essential for efficient motility. Additionally, our studies reveal that autophagosomes associate with FAs primarily during disassembly, suggesting autophagy locally facilitates the destabilization of cell-matrix contact sites. Furthermore, we identify the selective autophagy cargo receptor neighbor of BRCA1 (NBR1) as a key mediator of autophagy-dependent FA remodeling. NBR1 depletion impairs FA turnover and decreases targeting of autophagosomes to FAs, whereas ectopic expression of autophagy-competent, but not autophagy-defective, NBR1 enhances FA disassembly and reduces FA lifetime during migration. Our findings provide mechanistic insight into how autophagy promotes migration by revealing a requirement for NBR1-mediated selective autophagy in enabling FA disassembly in motile cells.
自噬是一种分解代谢途径,涉及将细胞内容物隔离到双膜囊泡即自噬体中。尽管最近的研究表明自噬支持细胞迁移,但其潜在机制仍不清楚。通过活细胞成像,我们发现自噬促进最佳迁移速率,并促进细胞与基质黏着斑(FAs)的动态组装和拆卸,这对有效运动至关重要。此外,我们的研究表明,自噬体主要在拆卸过程中与FAs相关联,这表明自噬在局部促进细胞与基质接触位点的不稳定。此外,我们确定乳腺癌1号基因(BRCA1)的选择性自噬货物受体邻居(NBR1)是自噬依赖性FA重塑的关键介质。NBR1的缺失会损害FA的周转,并减少自噬体对FAs的靶向,而具有自噬能力但无自噬缺陷的NBR1的异位表达会增强FA的拆卸,并缩短迁移过程中FA的寿命。我们的研究结果揭示了运动细胞中NBR1介导的选择性自噬在实现FA拆卸中的必要性,从而为自噬如何促进迁移提供了机制上的见解。