The Axonal ER Couples Translation and Secretion Machineries for Local Delivery of Axonal Transmembrane Proteins to Promote Axonal Development

Proper neuronal development and function rely on the polarized sorting of transmembrane proteins (TMPs) to their distinct somatodendritic or axonal domains. Most TMPs follow a conventional secretory pathway confined to the cell soma, where they are translated at the rough ER, exit through ER exit sites (ERES) to reach the Golgi apparatus (GA), prior to their delivery to the plasma membrane (PM). Intriguingly, we recently found that many mRNAs encoding TMPs are associated with the axonally-enriched ER-protein P180, which facilitates axonal ER-ribosome interaction and regulates local translation. Given the absence of the GA in the axon, it remains unknown how locally synthesized TMPs leave the ER and reach the axonal PM. Here, we visualized the translation of different axonal TMPs within the axon and followed their trafficking from the ER. We found that a fraction of neosynthesized cargos follow an unconventional route, exiting the axonal ER and reaching the PM independent of the GA. Notably, we identified axonal ERES components tightly associated with the axonal ER. Removal of these components prevents TMP exit from the axonal ER, while addition of external cues increases the number of axonal ERES and Golgi-bypassing cargos. Moreover, we identified the ER-translation regulator HDLBP and the NRZ-SEC22B vesicular tether complex associated with axonal ERES and involved in unconventional secretion. Local removal of axonal ERES components or depletion of these identified players causes defects in axon growth and bouton assembly. We propose a novel mechanism coupling local TMP translation and secretion to the PM at the axonal ER, which is essential for neuronal development. HIGHLIGHTS ### Competing Interest Statement The authors have declared no competing interest. European Research Council, https://ror.org/0472cxd90, ERC-StG 950617, ERC-StG 101163280 Target ALS, https://ror.org/03fsqvg68, NI-2024-NAI-S5