Kawaguchi, K., Hama, Y., Yoshikawa, H., Nishino, K., Morimoto, K., Nakamura, T., Koizumi, M., Sakamaki, Y., Abe, K., Kakuta, S., Ichimura, K., Ikeda, F., Kosako, H., Fujita, N. (2026). Linear ubiquitination triggers Amph-mediated T-tubule biogenesis.  Sci. Adv. 12(2): eady4934.

FBrf0264320

Research paper

Transverse tubules (T-tubules) are invaginations of the muscle plasma membrane that facilitate rapid transmission of action potentials, ensuring synchronized muscle contraction. Despite their essential role in muscle physiology, the mechanisms underlying T-tubule formation remain elusive. Here, we identify LUBEL/RNF31, a ubiquitin E3 ligase responsible for linear (M1-linked) ubiquitination, as a key regulator of T-tubule biogenesis in Drosophila. Loss of LUBEL leads to Amphiphysin (Amph)-positive membrane sheets instead of tubular networks. The ubiquitin ligase activity of LUBEL and direct interaction with Amph, a BAR domain protein involved in membrane tubulation, are crucial for proper T-tubule morphology. LUBEL and M1-linked ubiquitin chains assemble into puncta on membranes through multivalent interactions, facilitating Amph-mediated tubulation. Notably, the Amph-LUBEL/RNF31 interaction is evolutionarily conserved across species, underscoring a fundamental role for linear ubiquitination in membrane remodeling. Our findings uncover an unexpected function of linear ubiquitination in membrane deformation driven by BAR proteins.

PMC12778051 (PMC) (EuropePMC)