Tetraspanin-6 negatively regulates exosome production

Significance Exosomes have emerged as extracellular organelles controlling cell-cell communication in health and disease. Poor knowledge of the molecular mechanisms supporting exosome formation limits rational exploitation of exosomes in diagnostics and therapeutics. Tetraspanins and syndecans, two families of membrane scaffold proteins, compose characteristic exosomal cargo. Syndecans are versatile coreceptors and tetraspanins are well known to control the traffic of various signaling molecules, but the interconnection between these two families remains largely unexplored. Here we identify a functional crosstalk between specific members of the tetraspanin and syndecan families in exosome formation. Specifically, we demonstrate the importance of tetraspanin-6-controlled syndecan-4-syntenin trafficking in the balance between exosomal secretion and lysosomal degradation. This work reveals that syndecan-tetraspanin membrane scaffolds cooperate to dictate exosome formation.