Endosomes serve as signaling platforms for RIG-I ubiquitination and activation

Area of Science:

• Immunology
• Cell Biology
• Virology

Background:

• RIG-I-like receptors (RLRs) are crucial cytosolic sensors for detecting viral RNA and initiating antiviral responses.
• RLR activation involves polyubiquitination and oligomerization, but the role of subcellular organelles in these processes is unclear.
• Endosomal adaptor TAPE is known to regulate Toll-like receptor and RLR pathways.

Purpose of the Study:

• To investigate the role of endosomes in RIG-I signaling and activation.
• To elucidate the mechanism by which endosomes facilitate RIG-I posttranslational modifications and complex formation.
• To determine the in vivo significance of endosomal involvement in RIG-I-mediated antiviral immunity.

Main Methods:

• Utilized cell-based assays to track RIG-I translocation and complex formation on endosomes.
• Employed genetic ablation of endosomes to assess the impact on RIG-I signaling.
• Investigated the role of TAPE in mediating RIG-I and TRIM25 interactions and ubiquitination.
• Assessed type I interferon activation in TAPE-deficient myeloid cells and in vivo models upon viral challenge.

Main Results:

• Endosomes serve as platforms for RIG-I polyubiquitination and the formation of signaling complexes.
• RIG-I translocates to endosomes upon activation, and endosome ablation impairs type I interferon signaling.
• TAPE is essential for mediating RIG-I and TRIM25 interaction and subsequent polyubiquitination.
• TAPE deficiency in myeloid cells leads to impaired antiviral responses and increased susceptibility to RNA virus infection.

Conclusions:

• Endosomes are critical signaling platforms that facilitate RIG-I activation and antiviral immunity.
• The TAPE-dependent recruitment of RIG-I to endosomes is a key step in initiating robust type I interferon responses.
• Targeting endosomal pathways may offer new strategies for enhancing antiviral therapies.