The transport of secretory proteins from the endoplasmic reticulum (ER) to the
Golgi depends on COPII-coated vesicles. While the basic principles of the
COPII machinery have been identified, it remains largely unknown how COPII
transport is regulated to accommodate tissue- or activation-specific
differences in cargo load and identity. Here we show that activation-induced
alternative splicing of Sec16 controls adaptation of COPII transport to
increased secretory cargo upon T-cell activation. Using splice-site blocking
morpholinos and CRISPR/Cas9-mediated genome engineering, we show that the
number of ER exit sites, COPII dynamics and transport efficiency depend on
Sec16 alternative splicing. As the mechanistic basis, we suggest the
C-terminal Sec16 domain to be a splicing-controlled protein interaction
platform, with individual isoforms showing differential abilities to recruit
COPII components. Our work connects the COPII pathway with alternative
splicing, adding a new regulatory layer to protein secretion and its
adaptation to changing cellular environments