MAP4-MAP7D1 partitioning on tyrosinated-detyrosinated microtubules coordinates lysosome positioning in nutrient signalling

Abstract Microtubule-associated proteins (MAPs) and tubulin post-translational modifications (PTMs) together shape a dynamic intracellular landscape for motor-driven transport, yet how the “MAP-PTM crosstalk” regulates organelle positioning remains unclear. Here, we show that MAP4 and MAP7D1 selectively partition onto distinct microtubule subsets demarcated by tyrosination and detyrosination, respectively, creating specialized tracks for kinesin motors. MAP4’s preferential binding depends on its projection domain, while expanded microtubule lattice states mediate MAP7D1’s enrichment on detyrosinated microtubules. Remarkably, rigor kinesin-1 (KIF5B-R) predominantly localizes to detyrosinated, MAP7D1-coated tracks, whereas rigor kinesin-3 (KIF1A) prefers tyrosinated, MAP4-decorated microtubules. We further find that the local density of MAP4 and MAP7D1 on microtubules fine-tunes lysosomal movement and directional transport. Moreover, MAP density is modulated to coordinate lysosomal reorganization in response to nutrient availability. During starvation MAP7D1 density on microtubules increases while MAP4 density decreases, localizing lysosomes to the perinuclear region. Conversely, with nutrient stimulation, MAPD1 density declines, allowing lysosomes to migrate towards the cell periphery. Altering the cellular levels of MAP4 and MAP7D1, either up or down, hinders lysosomal motility, trapping them near the nucleus and impairing their responsiveness to nutrient stimulation. Together, our findings reveal two distinct MAP–PTM circuits, a MAP4–tyrosination–kinesin-3 axis and a MAP7D1– detyrosination–kinesin-1 axis, that govern lysosome positioning for nutrient signaling, highlighting the combinatorial logic of MAP and tubulin codes in shaping microtubule function. Competing Interest Statement The authors have declared no competing interest.