Trashed proteins may help immune system

Imagine an automobile factory where one out of three newly built cars had defects so severe it was instantly scrapped and its parts recycled. No business would accept such wastefulness.

Surprisingly, human cells seem to tolerate that sort of inefficiency in building proteins. A report in the April 13 Nature indicates that up to 30 percent of proteins get recycled as soon as they roll off the cellular assembly line, apparently because the molecules haven’t folded into their proper three-dimensional shapes.

The immune system may exploit this seemingly wasteful process, say the researchers. To alert the body’s immune system to a viral infection, they suggest, a cell can use the deformed viral proteins that it builds.

This hypothesis emerged about 5 years ago when Jonathan W. Yewdell, Luis C. Antón, and Jack R. Bennink of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Md., pondered how immune cells react quickly to a virus. To eliminate an infected cell, immune cells must first detect fragments of viral proteins on its surface.

Scientists had thought that such fragments were conveyed to the surface only after viral proteins had aged and been chewed up by proteasomes, tube-shaped cellular structures that break apart proteins that have outlived their usefulness. This delay, however, would allow a virus to spread before an immune cell could destroy the infected cell.

The NIAID team wondered if proteasomes instead have immediate access to some of the viral molecules made by ribosomes, the protein-building factories in cells. Perhaps many new proteins, whether cellular or viral, misfold and instantly get degraded by proteasomes, the scientists proposed. They refer to such imperfect molecules as defective ribosomal products, or DRiPs.

To gauge the number of DRiPs a cell makes, these researchers worked with Ulrich Schubert, also of NIAID, to infuse cells with a radioactively labeled amino acid. They then treated some of the cells with compounds that inhibit proteasomes and compared the amount of radioactively labeled proteins in treated and untreated cells. “You detect a lot more proteins when you add a proteasome inhibitor,” says Yewdell.

The scientists estimated how many new proteins the proteasomes normally tear apart. In their initial experiments, they used cancer cells and found that nearly two-thirds of the proteins were apparently DRiPs. Healthy cells seem to immediately discard one-third of new proteins, the NIAID researchers report in Nature.

Some investigators question whether cells are truly that wasteful, admits Yewdell. Indeed, Alfred L. Goldberg of Harvard Medical School in Boston, a pioneer in proteasome research, suggests that the proteins that accumulate in cells given proteasome inhibitors aren’t misfolded but simply short-lived proteins that have fulfilled their purposes and would normally be destroyed.

Yewdell and his colleagues, however, have also shown that HIV-infected cells given proteasome inhibitors experience a buildup of a long-lived viral protein called Gag. They believe that this accumulation consists of newly minted but misfolded versions of the protein.

In a second Nature paper supporting the NIAID scientists’ theory, Jacques Neefjes of the Netherlands Cancer Institute in Amsterdam and his colleagues report that a molecule that helps place viral fragments on the cell surface obtains those fragments from freshly built proteins.

“The immune system is not condemned to wait until properly folded proteins have been degraded and their fragments presented for recognition. Instead, by using the DRiP shortcut, the immune system can initiate countermeasures while the foreign proteins are still being produced,” conclude Hansjörg Schild and Hans-Georg  Rammensee of the Institute for Cell Biology in Tübingen, Germany, in an accompanying commentary.