MAPK8IP1/JIP1 regulates the trafficking of autophagosomes in neurons

Abstract

Autophagy is a spatially regulated process in axons; autophagosomes form preferentially in the distal axon tip then move actively and processively toward the cell body. Despite the primarily unidirectional transport observed in live-cell imaging experiments, both anterograde-directed KIF5/kinesin-1 motors and retrograde-directed dynein motors are tightly associated with axonal autophagosomes. Here, we discuss our recent work identifying the scaffolding protein MAPK8IP1/JIP1 (mitogen-activated protein kinase 8 interacting protein 1) as a key regulator of autophagosome transport in neurons. MAPK8IP1 tightly coordinates motor activity to ensure the fidelity of retrograde autophagosome transport in the axon.

Keywords: JIP1; LC3; LIR; MKP1; autophagosomes; axonal transport; dynactin; dynein; kinesin; motor regulation.

Figure 1.

MAPK8IP 1 regulates the axonal transport of 2 different organelles, APP-positive vesicles and autophagosomes. (A) MAPK8IP 1 exists as 2 distinct motor complexes—an anterograde complex binds directly to KIF5 and activates kinesin motor activity, and a retrograde complex binds directly to the dynein activator dynactin. Phosphorylation at the S421 site in the KIF5-binding domain of MAPK8IP 1 regulates switching between these 2 complexes and, thus, determines the direction of APP transport. (B) Two mechanisms ensure that autophagosomes move exclusively in the retrograde direction in the axon. The phosphatase DUSP1, which robustly associates with MAPK8IP 1-positive autophagosomes, may maintain MAPK8IP 1 in the nonphosphorylated retrograde motor complex. Binding of LC3 to MAPK8IP 1 further deters binding and activation of KIF5. MT, microtubule.