JIP3 interacts with dynein and kinesin-1 to regulate bidirectional organelle transport

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• JIP3 (JNK interacting protein 3) is a scaffold protein involved in MAP kinase signaling and motor protein transport.
• JIP3 regulates lysosome accumulation in axons, but its precise interaction with dynein and kinesin-1 for organelle clearance is not fully understood.

Purpose of the Study:

• To elucidate the role of JIP3's interaction with dynein and kinesin-1 in organelle clearance within neuronal axons.
• To investigate the functional significance of the JIP3-dynein interaction mediated by the RH1 domain.

Main Methods:

• Biochemical assays to determine binding interactions between JIP3, dynein light intermediate chain (DLIC), and kinesin heavy chain.
• Generation and characterization of a separation-of-function JIP3 mutant in Caenorhabditis elegans.
• Analysis of organelle accumulation and transport in JIP3 mutant neurons.

Main Results:

• Human DLIC binds to the N-terminal RH1 domain of JIP3, JIP4, and RILP.
• A specific RH1 domain mutation disrupts DLIC binding but not kinesin heavy chain interaction.
• JIP3-bound dynein is essential for clearing endo-lysosomal organelles in C. elegans touch receptor neurons.
• Mutant JIP3 unable to bind DLIC leads to organelle accumulation at neurite tips, which can be rescued by a mutation affecting kinesin light chain binding.

Conclusions:

• JIP3's RH1 domain acts as a critical hub for coordinating cytoskeletal motor interactions.
• JIP3-bound dynein and kinesin-1 are both required for bidirectional organelle transport and clearance in axons.
• Dysregulation of JIP3-motor interactions contributes to lysosomal organelle accumulation in neurons.