2025/09/09 by Ha H. Nguyen, Noortje Kersten, Chun Hei Li +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · #RNA Research and Splicing #RNA Interference and Gene Delivery #RNA regulation and disease
paper · pdf · doi:10.1101/2025.09.09.674816
Abstract Neuronal development and function rely on the polarized sorting of transmembrane proteins (TMPs). Most TMPs follow a conventional secretory pathway confined to the cell soma, where ER-translated TMPs exit the ER through ERES to reach the Golgi, prior to PM delivery. We recently found that the axonal ER regulates local translation; however, how this is linked to secretion remains unknown. Here, we find that axonally translated TMPs exit the ER and reach the axonal PM via an ERES-dependent/Golgi-independent route. Intriguingly, we uncover a feedback loop linking translation and secretion at axonal ERES. HDLBP-dependent TMP synthesis regulates ERES formation, and axonal ERES in turn modulate TMP translation. Subsequently, the NRZ-SEC22B tethering complex links local TMP ER exit to PM delivery, dependent on ER-PM contacts. Axonal ERES and these associated molecular players support axon growth and bouton assembly. We propose a novel mechanism in which coupling of axonal TMP synthesis and secretion is essential for neuronal development.