Scientists thought it was all about sugar. But this glucose transporter is also involved in virus defense, University of Connecticut researchers report in the 2024 December issue of Nature Immunology.

Glucose transporter 4 (GLUT4) is mostly found in fatty tissue, skeletal and heart muscle. Its primary function is to pull glucose, a simple sugar the body uses as fuel, out of the blood and into cells for energy production and storage. If GLUT4 doesn’t do that essential job, the risk of Type 2 diabetes rises quickly. But now, researchers have found another role for GLUT4: during a viral infection it can tether molecules that would otherwise warn the immune system of an infection.

It’s not surprising that GLUT4 serves more than one function; many molecules in the body do. What is surprising is that it suppresses the body’s anti-virus response. UConn School of Medicine immunologist Penghua Wang wondered why GLUT4 might do this.

Wang and his colleagues, graduate student Andrew G. Harrison and postdoctoral researcher Duomeng Yang, had first noticed an antiviral role for UBXN9 (of the UBXN family genes that Wang’s lab has been long working on) in mouse muscle cells.  UBXN9 ties down GLUT4 inside the cell and can release GLUT4 to the cell surface when needed. The researchers tested mouse skeletal muscle and human heart cells that had UBXN9 but lacked GLUT4 and found a boost to antiviral immunity.  It turned out that GLUT4 confined immune sensors to the cell surface, thus preventing them from working.

When the researchers infected mice with Coxsackie B virus, a major cause of viral myocarditis (heart inflammation), mice lacking GLUT4 had much less viral replication and myocarditis than normal mice.

“Why GLUT4 inhibits antiviral immunity, we don’t have the answer yet,” says Wang. “But we believe it could be beneficial, by inhibiting certain auto inflammatory diseases.” Other studies have observed that rare autoimmune muscle disorders in humans are associated with GLUT4 dysfunction.

Wang suggests that GLUT4 inhibitors might be therapeutically effective against certain viral infections and the heart inflammation they cause.