Membrane Protein Trafficking in Endocytic Pathways

Membrane protein trafficking via endocytic pathways is essential for the regulation of receptor signalling, nutrient uptake and membrane homeostasis. Following internalisation from the plasma membrane, proteins are delivered to early endosomes where cargo is sorted for recycling back to the surface, retrograde transport to the trans-Golgi network or progression towards late endosomes and lysosomes for degradation. This decision point relies on coordinated actions of coat complexes, adaptors, small GTPases and cytoskeletal motors that sculpt endosomal membranes and direct transport carriers. Key sorting assemblies include the retromer complex, which retrieves specific transmembrane proteins from endosomes, and the related CCC and WASH complexes that regulate actin dynamics to facilitate carrier formation. Small GTPases such as Rab5 and Rab7 define endosomal identity and recruit effectors that mediate vesicle budding, motility and fusion. Autophagic pathways intersect with endocytic trafficking, diverting selected membrane proteins for lysosomal turnover and contributing to cellular quality control. Dysregulation of these processes underlies a spectrum of human diseases, including neurodegeneration, immune disorders and hypercholesterolaemia, and has become a fertile ground for therapeutic intervention.

Research from Nature Portfolio

Recent studies using integrated multi-omic approaches have provided refined insights into retromer-mediated regulation of endo-lysosomal health. Comprehensive proteomic and transcriptomic profiling in human neuronal models revealed that retromer dysfunction leads to broad lysosomal proteome remodelling, impaired autophagic lysosome reformation and compensatory increases in lysosomal exocytosis, underlining its neuroprotective role. Complementary work has demonstrated that the CCC and WASH complexes are indispensable for endosomal sorting of the low-density lipoprotein receptor. Mutations in CCC components result in receptor mislocalisation, enhanced lysosomal degradation and reduced lipid uptake, illuminating how endocytic trafficking governs systemic cholesterol homeostasis and suggesting potential targets for hypercholesterolaemia treatment.

Membrane Protein Trafficking in Endocytic Pathways publication trend

The graph below shows the total number of articles in membrane protein trafficking in endocytic pathways across all publications each year (not limited to Nature Index journals).

Technical terms

Endocytic pathway: Cellular system for internalising extracellular material via vesicles and sorting it through successive endosomal compartments.

Retromer complex: Multisubunit assembly that recognises and retrieves specific transmembrane cargos from endosomes for recycling or retrograde transport.

WASH complex: Actin-nucleating assembly recruited to endosomal membranes to drive the formation of transport carriers.

Small GTPase: Enzyme that toggles between active GTP-bound and inactive GDP-bound states to regulate membrane trafficking events.

Autophagosome: Double-membrane vesicle that sequesters cytoplasmic constituents for delivery to lysosomes.

Late endosome: Maturing compartment that directs sorted cargo towards lysosomal degradation or recycling routes.

References

1. Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome. Cell (2023).
2. Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health. Nature Communications (2023).
3. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nature Communications (2016).
4. Multiple Roles of the Small GTPase Rab7. Cells (2016).
5. Control of RAB7 activity and localization through the retromer‐TBC1D5 complex enables RAB7‐dependent mitophagy. The EMBO Journal (2017).