Following synthesis in the cytosol, most eukaryotic proteins must cross one or more membranes to reach their site of function. Proteins that are destined for the secretory pathway are normally targeted to the endoplasmic reticulum (ER) and translocated co-translationally across its membrane. However, some short secretory proteins [such as preprocecropin A (ppcecA), a moth anti-microbial peptide precursor] are post-translationally translocated across the ER membrane in insects and amphibians. Here, Stephen High and co-workers (p. ) identify two human secretory proteins – apelin and statherin – as bona fide substrates for post-translational translocation across the ER membrane. They show that ppcecA, apelin and statherin bind to the ATPase TRC40 (also known as ASNA1), which is involved in the post-translational delivery of tail-anchored proteins to the ER membrane, and that this association facilitates their delivery to the ER membrane. ppcecA can also be delivered to the ER by a TRC40-independent pathway. However, on arrival at the ER membrane, all three proteins are transported across the membrane by the Sec61 translocon, irrespective of the delivery route they employed. Thus, the authors speculate, post-translational translocation of secretory proteins in higher eukaryotes might be more prevalent than previously thought.
