Details

Autor(en) / Beteiligte

• Fu, Meng-meng
• Nirschl, Jeffrey J.
• Holzbaur, Erika L.F.

Titel

LC3 Binding to the Scaffolding Protein JIP1 Regulates Processive Dynein-Driven Transport of Autophagosomes

Ist Teil von

• Developmental cell, 2014-06, Vol.29 (5), p.577-590

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• Autophagy is essential for maintaining cellular homeostasis in neurons, where autophagosomes undergo robust unidirectional retrograde transport along axons. We find that the motor scaffolding protein JIP1 binds directly to the autophagosome adaptor LC3 via a conserved LIR motif. This interaction is required for the initial exit of autophagosomes from the distal axon, for sustained retrograde transport along the midaxon, and for autophagosomal maturation in the proximal axon. JIP1 binds directly to the dynein activator dynactin but also binds to and activates kinesin-1 in a phosphorylation-dependent manner. Following JIP1 depletion, phosphodeficient JIP1-S421A rescues retrograde transport, while phosphomimetic JIP1-S421D aberrantly activates anterograde transport. During normal autophagosome transport, residue S421 of JIP1 may be maintained in a dephosphorylated state by autophagosome-associated MKP1 phosphatase. Moreover, binding of LC3 to JIP1 competitively disrupts JIP1-mediated activation of kinesin. Thus, dual mechanisms prevent aberrant activation of kinesin to ensure robust retrograde transport of autophagosomes along the axon. [Display omitted] •Retrograde axonal transport of autophagosomes requires the scaffolding protein JIP1•JIP1 binds directly to the autophagosome protein LC3 via a conserved LIR motif•LC3-binding to JIP1 blocks the JIP1-mediated activation of kinesin-1 motor activity•JIP1 dephosphorylation by organelle-bound MKP1 may also block kinesin-1 activation Axoal autophagosomes move in the retrograde direction. Fu et al. show that this unidirectional motility is driven by direct binding of the motor scaffolding protein JIP1 to the autophagosome adaptor LC3. Two mechanisms ensure that autophagosomes do not move in the anterograde direction: maintaining unphosphorylated JIP1 and blocking kinesin activation.