In eukaryotes, most secreted proteins involved in intercellular communication are exported from cells by a highly evolved and conserved pathway, classically termed the conventional secretory pathway. Briefly, proteins such as antibodies, collagens, mucins, cytokines, hormones, and neurotransmitters contain a signal sequence which directs their translocation into the Endoplasmic Reticulum (ER). These proteins are then transported to the Golgi apparatus and subsequently to their respective destinations within the cell and to cell’s exterior. Over the last five decades, we have gained a clear understanding of the basic machinery underlying these processes of cargo capture and transfer between compartments en route to their exit from cells.
However, new discoveries have recently emphasized the critical role of alternative exocytic routes for the secretion of a growing number of proteins lacking signal sequence (or leaderless proteins) to enter the ER-Golgi pathway. This process is called unconventional protein secretion and represent a major gap in our understanding of mechanisms supporting protein trafficking and secretion.
Mechanisms proposed for unconventional protein secretion include either direct translocation of leaderless proteins across the plasma membrane, or the mobilization of vesicular intermediates that are derived from secretory autophagosomes, lysosomes, multivesicular bodies, or as shown in yeast, from a transient and hybrid compartment formed of Golgi and endosome membranes called CUPS. Thus, a general picture in this emerging research field is that, in a cell type-dependent manner and linked to intrinsic demands or in response to environmental cues, intracellular compartments are remodelled and re-routed for secretion of leaderless proteins and pathogens such as viruses. Surprisingly, few functional factors have been clearly identified in these processes. In this context, and taking into account the key role of cargo proteins secreted unconventionally in health and disease conditions, there is an urgent need to gain mechanistic insights into this unconventional mode of secretion. By understanding this crucial biological process, we aim to make important advances into basic mechanisms that can then be employed for biomedical applications.
This Research Topic aims to gather contributions illustrating recent advances on unconventional protein secretion, from fundamental knowledge to dysregulations in pathological conditions including cancer, infection and neurodegenerative diseases. Areas to be covered may include, but are not limited to:
- External cues and signaling pathways that trigger or regulate the process of unconventional protein secretion.
- The molecular machinery (ex. chaperones, receptors, protein channels) required for leaderless protein packaging into membrane intermediates or for translocation across the plasma membrane.
- Amino-acid sequences, post-translational modifications as well as protein conformation changes that direct leaderless proteins through unconventional secretory pathways.
- Organelle crosstalk and dynamics, and intracellular trafficking pathway interconnections.
- Advances in methodology and new model organisms to study unconventional protein secretion during development and in human diseases.
We welcome Original Research articles, Methods, Reviews and mini-Review articles that will provide interesting results, trends and concepts in this growing research field.
In eukaryotes, most secreted proteins involved in intercellular communication are exported from cells by a highly evolved and conserved pathway, classically termed the conventional secretory pathway. Briefly, proteins such as antibodies, collagens, mucins, cytokines, hormones, and neurotransmitters contain a signal sequence which directs their translocation into the Endoplasmic Reticulum (ER). These proteins are then transported to the Golgi apparatus and subsequently to their respective destinations within the cell and to cell’s exterior. Over the last five decades, we have gained a clear understanding of the basic machinery underlying these processes of cargo capture and transfer between compartments en route to their exit from cells.
However, new discoveries have recently emphasized the critical role of alternative exocytic routes for the secretion of a growing number of proteins lacking signal sequence (or leaderless proteins) to enter the ER-Golgi pathway. This process is called unconventional protein secretion and represent a major gap in our understanding of mechanisms supporting protein trafficking and secretion.
Mechanisms proposed for unconventional protein secretion include either direct translocation of leaderless proteins across the plasma membrane, or the mobilization of vesicular intermediates that are derived from secretory autophagosomes, lysosomes, multivesicular bodies, or as shown in yeast, from a transient and hybrid compartment formed of Golgi and endosome membranes called CUPS. Thus, a general picture in this emerging research field is that, in a cell type-dependent manner and linked to intrinsic demands or in response to environmental cues, intracellular compartments are remodelled and re-routed for secretion of leaderless proteins and pathogens such as viruses. Surprisingly, few functional factors have been clearly identified in these processes. In this context, and taking into account the key role of cargo proteins secreted unconventionally in health and disease conditions, there is an urgent need to gain mechanistic insights into this unconventional mode of secretion. By understanding this crucial biological process, we aim to make important advances into basic mechanisms that can then be employed for biomedical applications.
This Research Topic aims to gather contributions illustrating recent advances on unconventional protein secretion, from fundamental knowledge to dysregulations in pathological conditions including cancer, infection and neurodegenerative diseases. Areas to be covered may include, but are not limited to:
- External cues and signaling pathways that trigger or regulate the process of unconventional protein secretion.
- The molecular machinery (ex. chaperones, receptors, protein channels) required for leaderless protein packaging into membrane intermediates or for translocation across the plasma membrane.
- Amino-acid sequences, post-translational modifications as well as protein conformation changes that direct leaderless proteins through unconventional secretory pathways.
- Organelle crosstalk and dynamics, and intracellular trafficking pathway interconnections.
- Advances in methodology and new model organisms to study unconventional protein secretion during development and in human diseases.
We welcome Original Research articles, Methods, Reviews and mini-Review articles that will provide interesting results, trends and concepts in this growing research field.
