Nuclear envelope budding enables export of large transcripts in muscle cells

Nuclear envelope (NE) budding (NEB) has emerged as an alternative route for nuclear export of viral particles that are too large to pass through the nuclear pore complex. Yet the significance of this unconventional export pathway for large endogenous cargoes in mammalian cells has remained largely unexplored. Here, we use a combination of electron and fluorescence microscopy to demonstrate that NEB events occur following myoblast differentiation into myotubes and concomitant with the expression of extremely long muscle-specific transcripts. We show that NE buds are derived from the inner nuclear membrane, contain internal vesicles, and are specifically enriched with long sarcomeric transcripts. We identify a role for the protein UAP56-interacting factor (UIF) in regulating mRNA cargo targeting into NE buds and show that this pathway requires the endosomal sorting complex required transport III (ESCRT-III) membrane remodeling machinery. Our findings uncover a non-canonical pathway for large transcript nuclear export in muscle cells and provide insight into its mechanism.