Virus Control of Trafficking from Sorting Endosomes

Area of Science:

• Cell Biology
• Virology
• Molecular Biology

Background:

• Cell surface protein maintenance is crucial for cellular sensing and response.
• Endocytic trafficking pathways, including sorting endosomes (SEs), regulate protein recycling and degradation.
• Human cytomegalovirus (HCMV) infection reorganizes host endocytic membranes.

Purpose of the Study:

• To investigate how HCMV infection affects the trafficking of internalized clathrin-independent endocytosis (CIE) cargo.
• To identify host factors and mechanisms involved in HCMV-induced alterations of endocytic sorting.
• To explore potential therapeutic targets for restoring normal protein trafficking during HCMV infection.

Main Methods:

• Analysis of clathrin-independent endocytosis (CIE) cargo localization in HCMV-infected cells.
• Assessment of ADP ribosylation factor 6 (ARF6) association with sorting endosome membranes.
• Overexpression of ubiquitin-specific protease 6 (USP6/TRE17) to evaluate its effect on protein trafficking.

Main Results:

• HCMV retains internalized CIE cargo proteins and the regulator ARF6 in virally reprogrammed sorting endosomes.
• Expression of USP6/TRE17 partially restores the trafficking of ARF6 and some of its cargo to the cell surface.
• The protease activity of TRE17 is essential for rescuing ARF6 and its cargo from sorting endosome retention.

Conclusions:

• HCMV profoundly reprograms host endocytic trafficking, selectively altering cargo sorting fates.
• A novel ubiquitin-regulated checkpoint at sorting endosomes may control cargo recycling during HCMV infection.
• Targeting this checkpoint with USP6/TRE17 offers a potential strategy to counteract HCMV-induced trafficking defects.