The microtubule associated protein 4 (MAP4) sweeps organelles towards the nucleus by weakening the kinesin motor

Regulation of organelle transport by molecular motors along the cytoskeletal microtubules is central to maintaining cellular functions. We show that the ubiquitous tau-related protein, MAP4, can skew the bidirectional transport of organelles towards the microtubule minus-ends. This is triggered by MAP4 phosphorylation, mediated by the kinase GSK3β. We demonstrate that, upon phosphorylation, MAP4 tethers the cargo to the microtubules, and impairs the ability of the plus-end motor kinesin-1 to generate force. Consistent with this, MAP4 physically interacts with dynein and dynactin and associates with the cargo-motor complex through its projection domain when phosphorylated. Organelles tethered to the microtubule through MAP4 accumulate perinuclearly, and abolishing this tether by overexpressing MAP4 subdomains leads to organelle dispersal. Similarly, perinuclear clustering of organelles is rescued upon pharmacological inhibition of dynein, confirming the ability of kinesin to inch along, albeit inefficiently, in the presence of phosphorylated MAP4. These findings have broad biological significance because of the ubiquity of MAP4 and the involvement of GSK3β in multiple diseases, more specifically in cancer, where MAP4-dependent redistribution of organelles may be prevalent in cancer cells, as we demonstrate for mitochondria in lung carcinoma epithelial cells.