Sorting nexin 5 mediates virus-induced autophagy and immunity

Area of Science:

• Immunology and Cell Biology
• Molecular mechanisms of autophagy and viral defense

Background:

• Autophagy, a cellular degradation process, plays a vital role in immunity and host defense against pathogens.
• The precise mechanisms initiating autophagy in response to viral infections remain incompletely understood.

Purpose of the Study:

• To identify host factors essential for initiating autophagy during viral infection.
• To elucidate the molecular mechanism by which autophagy is triggered by viruses.

Main Methods:

• Genome-wide short interfering RNA (siRNA) screens to identify essential genes.
• In vitro viral infection assays and in vivo studies using Snx5 knockout mice.
• Biochemical analyses of protein interactions, enzyme activity, and lipid production.

Main Results:

• Sorting nexin 5 (SNX5) is identified as essential for virus-induced autophagy, but not basal or stress-induced autophagy.
• SNX5 deficiency increases cellular susceptibility to viral infection and enhances lethality in mice.
• SNX5 interacts with the PI3KC3-C1 complex, enhancing its activity and promoting PtdIns(3)P generation at endosomes for viral clearance.

Conclusions:

• SNX5 acts as a critical mediator for initiating autophagy specifically during viral infections.
• The SNX5-dependent activation of PI3KC3-C1 at endosomes represents a novel mechanism for host defense against viruses.