Buonomo Viviana, Lohachova Kateryna, Reggio Alessio, Cano-Franco Sara, Cillo Michele, Santorelli Lucia, Venditti Rossella, Polishchuk Elena, Peluso Ivana, Brunello Lorene, Cirillo Carmine, Petrosino Sara, Silva Malan, De Cegli Rossella, Di Bartolomeo Sabrina, Gargioli Cesare, Swuec Paolo, Cortese Mirko, Stolz Alexandra, Bhaskara Ramachandra M, Grumati Paolo
Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.
Department of Clinical Medicine and Surgery, Federico II University, 80131, Naples, Italy.
EMBO J. 2025 Feb;44(4):1039-1073. doi: 10.1038/s44318-024-00356-2. Epub 2025 Jan 6.
Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, is an important regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER is reorganized. Knocking out both FAM134B isoforms in myotubes results in an aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine-tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells.
内质网（ER）可塑性和内质网自噬是维持内质网动态平衡所必需的相互交织的过程。我们研究了内质网自噬受体FAM134B的两种异构体在调节成肌细胞分化过程中内质网重塑方面的相互作用。在肌生成过程中，典型的FAM134B1被降解，而其异构体FAM134B2在转录水平上上调。这种偏向FAM134B2的转变是肌生成过程中内质网形态的重要调节因子。FAM134B2部分网状蛋白同源结构域具有刚性构象特征，能够有效地重塑内质网。FAM134B2的作用在分化的活跃阶段增强，通过内质网自噬导致内质网重构，当肌管成熟且内质网重新组织时，内质网又恢复到生理水平。在肌管中敲除两种FAM134B异构体导致蛋白质组景观异常和内质网扩张结构的形成，而FAM134B2的重新表达可以挽救这两种情况。我们的结果强调了FAM134B异构体和内质网自噬的精细调节如何在肌生成过程中协调内质网动态平衡，为了解肌肉细胞内质网稳态的分子机制提供了见解。
