UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons.
The conserved protein UNC-16 (JIP3) inhibits the active transport of some cell soma organelles, such as lysosomes, early endosomes, and Golgi, to the synaptic region of axons. However, little is known about UNC-16's organelle transport regulatory function, which is distinct from its Kinesin-1 adaptor function. We used an unc-16 suppressor screen in Caenorhabditis elegans to discover that UNC-16 acts through CDK-5 (Cdk5) and two conserved synapse assembly proteins: SAD-1 (SAD-A Kinase), and SYD-2 (Liprin-α). Genetic analysis of all combinations of double and triple mutants in unc-16(+) and unc-16(-) backgrounds showed that the three proteins (CDK-5, SAD-1, and SYD-2) are all part of the same organelle transport regulatory system, which we named the CSS system based on its founder proteins. Further genetic analysis revealed roles for SYD-1 (another synapse assembly protein) and STRADα (a SAD-1-interacting protein) in the CSS system. In an unc-16(-) background, loss of the CSS system improved the sluggish locomotion of unc-16 mutants, inhibited axonal lysosome accumulation, and led to the dynein-dependent accumulation of lysosomes in dendrites. Time-lapse imaging of lysosomes in CSS system mutants in unc-16(+) and unc-16(-) backgrounds revealed active transport defects consistent with the steady-state distributions of lysosomes. UNC-16 also uses the CSS system to regulate the distribution of early endosomes in neurons and, to a lesser extent, Golgi. The data reveal a new and unprecedented role for synapse assembly proteins, acting as part of the newly defined CSS system, in mediating UNC-16's organelle transport regulatory function.
Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
Stacey L
SL
Edwards
Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
Logan M
LM
Morrison
Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
Rosalina M
RM
Yorks
Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
Christopher M
CM
Hoover
Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104.
Soorajnath
S
Boominathan
Genetic Models of Disease Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 millerk@omrf.org.
Kenneth G
KG
Miller
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D001693:Biological Transport, Active; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C546590:STRD-1 protein, C elegans; C490598:SYD-2 protein, C elegans; C445161:unc-16 protein, C elegans; C421165:sad-1 protein, C elegans; D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases
Caenorhabditis elegans; Cdk5; JIP3; Liprin; SAD-A; axonal transport; dynein