Hitchhiking is a novel mechanism of organelle transport

项目总结

PROJECT SUMMARY The proper distribution of intracellular cargo is crucial for a wide variety of fundamental cellular processes, and defects in intracellular transport are particularly prevalent in neurodevelopmental and neurodegenerative disorders. However, how cargo transport is precisely organized such that the correct cargo is transported to the right place at the right time is not well understood. The long-term goals of this project are to understand how cargo transport is organized and executed in the cell, and to identify components that are adversely affected in diseased states. The majority of cargo in the cell is transported on microtubule tracks by the motor proteins dynein and kinesin. In the standard dogma of motor-driven transport, cargos are linked directly to motor proteins by adaptor molecules. The motor protein then transports the specific type of cargo to its destination. In contrast to this straightforward model of transport, the Reck-Peterson lab has recently co-discovered a novel mechanism of organelle transport, termed “hitchhiking”. Hitchhiking occurs when one type of cargo, rather than attaching directly to a motor, is tethered to and co-transported with another type of cargo. Our lab found that peroxisomes hitchhike on early endosomes in the model organism Aspergillus nidulans and identified the novel linker PxdA as being required for the co-transport of peroxisomes and early endosomes. However, whether hitchhiking is prevalent transport mechanism used to transport other organelle types and how PxdA mediates hitchhiking remain to be determined. This project will investigate the universality and mechanism of organelle hitchhiking in Aspergillus nidulans and hippocampal neurons using a combination of genetics, live cell imaging, and in vitro biochemistry. My aims are to 1) determine whether PxdA acts as a tether between peroxisomes and early endosomes, or whether it has additional functions, 2) determine whether lipid droplets and endoplasmic reticulum also hitchhike on EEs and if they require PxdA to do so, and 3) investigate whether organelle hitchhiking is conserved in hippocampal neurons and identify the linkers required for organelle hitchhiking in these cells. Together, my work will enhance our understanding of how hitchhiking works at a mechanistic level as well as its prevalence as a form of organelle transport.