SCM-1/SCAMP Maintains Microdomain Boundaries and Cargo Sorting within the Endosomal System.

Area of Science:

• Cell Biology
• Molecular Biology
• Membrane Trafficking

Background:

• Transmembrane cargo is sorted into distinct recycling or degradative microdomains on endosomes.
• The J-domain protein RME-8/DNAJC13 helps maintain microdomain boundaries by removing degradative machinery.

Purpose of the Study:

• To identify novel factors involved in endosomal microdomain organization and spatial boundary maintenance.
• To elucidate the role of the tetraspan protein SCM-1/SCAMP in endosomal sorting fidelity.

Main Methods:

• Proximity-dependent biotinylation screens in *C. elegans* and human cells to identify RME-8 interacting proteins.
• Analysis of microdomain organization and cargo sorting in *scm-1* (SCM-1) mutant *C. elegans* coelomocytes.
• Investigated cargo missorting of MIG-14/Wls and SNB-2/VAMP3 in wild-type and mutant backgrounds.

Main Results:

• SCM-1/SCAMP was identified as a key microdomain organizer, enriched in the recycling microdomain.
• In *scm-1* mutants, recycling and degradative microdomains lose spatial distinctness, leading to overlap.
• SCM-1 deficiency caused significant cargo missorting to late endosomes/lysosomes and delayed degradation of other cargo.

Conclusions:

• SCM-1 stabilizes endosomal microdomain boundaries, ensuring proper spatial organization.
• This boundary integrity is crucial for efficient recycling and degradation of transmembrane cargo.
• SCM-1 acts via a mechanism distinct from RME-8, highlighting multiple pathways for endosomal sorting fidelity.