Ubiquitination of α5β1 Integrin Controls Fibroblast Migration through Lysosomal Degradation of Fibronectin-Integrin Complexes

• Published in: Developmental cell Vol. 19; no. 1; pp. 148 - 159
• Main Authors: Lobert, Viola Hélène, Brech, Andreas, Pedersen, Nina Marie, Wesche, Jørgen, Oppelt, Angela, Malerød, Lene, Stenmark, Harald
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 01.07.2010; Cell Press
• Subjects: Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; CELLBIO; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; CELLBIO; Degradation; Regulation(control); Integrin; Migration; Lysosome; Development; Fibroblast; Fibronectin
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2010.06.010

Cell migration requires endocytosis and recycling of integrins, but it is not known whether degradation of these membrane proteins is involved. Here we demonstrate that in migrating cells, a fraction of the endocytosed fibronectin receptor, α5β1 integrin, is sorted into multivesicular endosomes together with fibronectin and degraded in lysosomes. This sorting requires fibronectin-induced ubiquitination of the α5 subunit, and the activity of the endosomal sorting complex required for transport (ESCRT) machinery, which interacts with α5β1 integrin. Importantly, we demonstrate that both α5 ubiquitination and ESCRT functions are required for proper migration of fibroblasts. We propose that ligand-mediated degradation of α5β1 integrin via the ESCRT pathway is required in order to prevent endosomal accumulation of ligand-bound integrins that might otherwise form nonproductive adhesion sites. Fibronectin and α5β1 integrin therefore are trafficked to lysosomes in a similar way to growth factors and their receptors. [Display omitted] ► α 5β1 integrin is ubiquitinated upon binding to fibronectin ► Fibronectin-bound α5β1 integrin is sorted in multivesicular endosomes ► Lysosomal trafficking of fibronectin and α5β1 integrin requires ESCRTs ► α5-fibronectin degradative sorting is required for fibroblast migration