MAP1A cleavage regulates TRIM46 transport to the axon in mature neurons

Polarised cargo transport is fundamental to neuronal function, ensuring the proper distribution of proteins and organelles between the cell body and axon. This process is tightly regulated at the proximal axon, where the enrichment of specific proteins organises the local cytoskeleton and directs intracellular trafficking. Although several microtubule-associated proteins (MAPs) have been implicated in axonal cargo transport during neuronal development, how protein localisation is maintained in mature neurons remains poorly understood. Here, we identify a previously unrecognised role for MAP1A in transporting TRIM46, a key organiser of the axonal microtubule cytoskeleton, to the axon of mature neurons, where it supports axon morphology. We show that MAP1A is enriched in the proximal axon and that its cleavage by Calpain-10 into heavy and light chains is required for TRIM46 localisation to this compartment. Mechanistically, the MAP1A light chain interacts with both TRIM46 and the tail domains of KIF3 motors, defining a transport complex that facilitates TRIM46 delivery to the proximal axon. Together, these findings establish proteolytic processing of a microtubule-associated protein as a mechanism regulating axonal protein distribution and neuronal polarity in mature neurons.