Internalization of plasma proteins, such as growth factor receptors, channels and nutrient transporters, is a highly active cellular process. For these proteins to maintain their predominant plasma membrane localization, the cell devotes a vast number of genes to the recycling of internalized surface proteins from the endosomal network back to the plasma membrane. This endosomal recycling process, by affecting a vast array of functionally diverse proteins, affects many aspects of cell physiology.
In a vast number of eukaryotic organisms the Wiskott Aldrich Syndrome Protein and SCAR homolog protein, or WASH, acting in the context of a pentameric molecular assembly, plays an essential role in endosomal sorting events. WASH functions as an activator of the Arp2/3 complex, leading to branched F-actin filament synthesis on the cytosolic surface of endosomal vesicles. This event is essential for endosomal recycling of plasma membrane proteins, and is also required for the proper organization of the endosomal network in the cell. Controlling the activity of WASH is therefore crucially important, and recent work has identified the COMMD/CCDC22/CCDC93 or CCC complex, as an evolutionarily conserved and essential regulator of WASH. Perturbations of these systems can have far-reaching consequences. For example, mutations in genes encoding subunits of WASH or CCC result in neurodevelopmental and cardiac anomalies, changes in copper excretion, elevation of plasma LDL cholesterol, and defective release of insulin in response to glucose, which can be traced to faulty trafficking of key receptors and transporters including Notch, ATP7A/ATP7B, LDLR and GLUT2.
Besides promoting the deposition of actin filaments, the WASH complex is linked to two highly related assemblies, retromer and retriever. Both of these complexes share a common subunit (VPS29), but retriever. Retromer, discovered in 1998 in yeast, is better understood and is involved in protein cargo selection as well vesicle coat generation. Retriever, identified nearly 20 years later, is specifically present in all eukaryotes that also possess WASH and CCC, and participates in endosomal recycling of specific cargo proteins. In this Research Topic, we aim to provide a comprehensive look at these systems and their interrelations, as well as highlight fundamental unanswered questions about their roles in the sorting process. In particular, we aim to cover the following topics:
The WASH complex:
• General overview of the WASH complex
• Structural understanding of WASH function
• Regulation of WASH activity
• Dysfunction of the WASH complex in human pathology
• Role of the WASH complex in nuclear organization and function
The CCC complex:
• The CCC complex and its role in endosomal sorting
• Structural studies to understand COMMD and CCC complex functionality
• Pathologic consequences of CCC dysfunction in animal models
• Regulation of immune function by the WASH and CCC complexes
• Dysfunction of the CCC complex in human pathology
• The CCC complex and transcriptional regulation
Retromer and Retriever:
• General overview of retromer
• Structural studies on retromer function
• Pathogen targeting of retromer function
• General overview of retriever
• Sorting nexins and their role in retromer and retriever function
• Retromer and retriever dysfunction in human disease
Internalization of plasma proteins, such as growth factor receptors, channels and nutrient transporters, is a highly active cellular process. For these proteins to maintain their predominant plasma membrane localization, the cell devotes a vast number of genes to the recycling of internalized surface proteins from the endosomal network back to the plasma membrane. This endosomal recycling process, by affecting a vast array of functionally diverse proteins, affects many aspects of cell physiology.
In a vast number of eukaryotic organisms the Wiskott Aldrich Syndrome Protein and SCAR homolog protein, or WASH, acting in the context of a pentameric molecular assembly, plays an essential role in endosomal sorting events. WASH functions as an activator of the Arp2/3 complex, leading to branched F-actin filament synthesis on the cytosolic surface of endosomal vesicles. This event is essential for endosomal recycling of plasma membrane proteins, and is also required for the proper organization of the endosomal network in the cell. Controlling the activity of WASH is therefore crucially important, and recent work has identified the COMMD/CCDC22/CCDC93 or CCC complex, as an evolutionarily conserved and essential regulator of WASH. Perturbations of these systems can have far-reaching consequences. For example, mutations in genes encoding subunits of WASH or CCC result in neurodevelopmental and cardiac anomalies, changes in copper excretion, elevation of plasma LDL cholesterol, and defective release of insulin in response to glucose, which can be traced to faulty trafficking of key receptors and transporters including Notch, ATP7A/ATP7B, LDLR and GLUT2.
Besides promoting the deposition of actin filaments, the WASH complex is linked to two highly related assemblies, retromer and retriever. Both of these complexes share a common subunit (VPS29), but retriever. Retromer, discovered in 1998 in yeast, is better understood and is involved in protein cargo selection as well vesicle coat generation. Retriever, identified nearly 20 years later, is specifically present in all eukaryotes that also possess WASH and CCC, and participates in endosomal recycling of specific cargo proteins. In this Research Topic, we aim to provide a comprehensive look at these systems and their interrelations, as well as highlight fundamental unanswered questions about their roles in the sorting process. In particular, we aim to cover the following topics:
The WASH complex:
• General overview of the WASH complex
• Structural understanding of WASH function
• Regulation of WASH activity
• Dysfunction of the WASH complex in human pathology
• Role of the WASH complex in nuclear organization and function
The CCC complex:
• The CCC complex and its role in endosomal sorting
• Structural studies to understand COMMD and CCC complex functionality
• Pathologic consequences of CCC dysfunction in animal models
• Regulation of immune function by the WASH and CCC complexes
• Dysfunction of the CCC complex in human pathology
• The CCC complex and transcriptional regulation
Retromer and Retriever:
• General overview of retromer
• Structural studies on retromer function
• Pathogen targeting of retromer function
• General overview of retriever
• Sorting nexins and their role in retromer and retriever function
• Retromer and retriever dysfunction in human disease
