TIM-1 Ubiquitination Mediates Dengue Virus Entry.

Area of Science:

• Virology
• Cell Biology
• Immunology

Background:

• Dengue virus (DENV) causes millions of human infections annually, posing a significant global health challenge.
• A definitive DENV receptor directly mediating virus internalization has remained elusive despite extensive research.

Purpose of the Study:

• To identify and characterize the specific host cell receptor responsible for Dengue virus entry.
• To elucidate the mechanism by which this receptor facilitates DENV internalization and infection.

Main Methods:

• Genetic ablation of the phosphatidylserine receptor TIM-1 in host cells.
• Total internal reflection fluorescence microscopy to visualize live cell infection dynamics.
• Analysis of TIM-1 ubiquitination and its interaction with intracellular trafficking machinery (STAM-1).

Main Results:

• Genetic deletion of TIM-1 significantly inhibited DENV infection, confirming its essential role.
• TIM-1 was observed within clathrin-coated pits, co-internalizing with DENV during entry.
• Ubiquitination of TIM-1 and its interaction with STAM-1 were critical for DENV endocytosis.

Conclusions:

• The phosphatidylserine receptor TIM-1 is identified as the first bona fide receptor for Dengue virus.
• TIM-1 actively mediates DENV endocytosis through clathrin-coated pits and ubiquitination-dependent pathways.
• This discovery provides a crucial target for developing novel antiviral strategies against DENV.