Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a provisional response from the authors.
Read more about eLife’s peer review process.Editors
- Reviewing EditorFrederic BardCentre de Recherche en Cancérologie de Marseille, MARSEILLE, France
- Senior EditorAmy AndreottiIowa State University, Ames, United States of America
Joint Public Review:
Lujan et al make a significant contribution to the field by elucidating the essential role of TGN46 in cargo sorting and soluble protein secretion. TGN46 is a prominent TGN protein that cycles to the plasma membrane and it has been used as a TGN marker for many years, but its function has been a fundamental mystery.
In parallel, it remains unclear how most secreted proteins are targeted from the Golgi to the cell surface. These molecules do not contain conserved sequence motifs or post-translation modifications such as lysosomal hydrolases. Cargo receptors for these secreted proteins have remained elusive.
Therefore, these investigations are likely to have a significant influence on the field.
To gain an insight into the molecular role of TGN46 in sorting, they systematically test the impact of the luminal, transmembrane, and cytosolic domains. Importantly and against the current thinking, they demonstrate that the luminal domain of TGN facilitates sorting. Interestingly, neither the cytosolic nor the length of the transmembrane domain of TGN46 plays a role in cargo export. The effects of TGN46 depletion are specific as membrane-associated VSVG remains unaffected.
Interestingly, TGN46 luminal domain also plays an important role in the intracellular and intra-Golgi localization of TGN46, and it contains a positive signal for Golgi export in CARTS. Rigorous, well-performed data support the experimental evidence.
A speculative part of the manuscript, with some accompanying experimental data, proposes that the luminal domain of TGN46 forms biomolecular condensates that help to capture cargo proteins for export.
One important point to discuss is that the effects of TGN46 KO are partial, suggesting that TGN46 stimulates the Golgi export of PAUF but is not essential for this process. The incomplete block is apparent in Fig 1 and in Fig 5D.