Linear ubiquitination triggers Amph-mediated T-tubule biogenesis

TL;DR

The study reveals that linear ubiquitination plays a key role in forming T-tubules in muscle cells through interactions with the protein Amph.

Contribution

The novel finding is that LUBEL/RNF31-mediated linear ubiquitination regulates T-tubule biogenesis via interactions with Amph in Drosophila.

Findings

LUBEL/RNF31 is essential for T-tubule formation in muscle cells.

Linear ubiquitination promotes membrane puncta assembly, which is crucial for Amph-mediated tubulation.

The LUBEL-Amph interaction is conserved across species, indicating a fundamental role in membrane remodeling.

Abstract

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.

Linear ubiquitination-driven puncta assembly on membranes triggers Amph-mediated T-tubule biogenesis in muscle cells.

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