EXOSOME BIOGENESIS AND FUNCTION
We want to understand how cells make exosomes, how they are trafficked through the body, and how they are taken up by neighboring and distant cells and organ systems.
Our Working Hypothesis
Our team discovered that exosome biogenesis (i) occurs primarily at the plasma membrane, that (ii) endocytosis greatly inhibits the exosomal secretion of proteins, and (iii) blocking endocytosis greatly increases the exosomal secretion of endocytosis signal-containing exosome cargo proteins. As for the fate of endocytosed cargo proteins, they appear to be (iv) delivered to the endosome membrane, (v) loaded into intraluminal vesicles (ILVs), and (vi) delivered to lysosomes and destroyed. However, ILVs can also be (vii) released as exosomes, a process that depends on endolysosomal exocytosis.
Major Ongoing Projects
1. What are the cis-acting signals and trans-acting factors that mediate the plasma membrane delivery and exosomal secretion of CD81, CD9, CD63, and other highly enriched exosome cargo proteins?
2. What happens to exosome cargo proteins after they are endocytosed? Are they loaded into ILVs? Are the ILVs degraded in lysosomes? Are the ILVs secreted as exosomes? Are there cis-acting signals and trans-acting factors that target proteins into ILVs that are degraded vs ILVs that are secreted as exosomes?
3. Does the intracellular sorting and exosomal secretion of exosome cargo proteins vary between different cell types? Do they change in response to extracellular signals? in cancer? in response to viral infections? And which aspects of exosome biogenesis have been conserved over the course of evolution and which vary?