Macrophages Lacking Ubiquitin-Binding Protein Stimulate Growth of Atherosclerotic Plaques

In a mouse model of atherosclerosis it was shown that while lack of the autophagy chaperone protein p62 prevented ubiquinated dysfunctional proteins from being sequestered in vesicles in the cytoplasm of macrophages, the presence of these proteins in the cell contributed to increased macrophage infiltration into atherosclerotic plaques and exacerbated atherosclerosis.

The ubiquitin-binding protein p62 (sequestosome-1) is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy, a catabolic cellular mechanism that degrades dysfunctional proteins and organelles.

Investigators at the Washington University School of Medicine (St. Louis, MO, USA) worked with a mouse model that lacked the critical autophagy protein ATG5. They found that exposure of macrophages to lipids that promote atherosclerosis increased the abundance of the autophagy chaperone protein p62, and that p62 co-localized with ubiquitinated proteins in cytoplasmic inclusions, which were characterized by insoluble protein aggregates. The ATG5-null macrophages developed further p62 accumulation at the sites of large cytoplasmic ubiquitin-positive inclusion bodies.

The formation of the cytoplasmic inclusions depended on p62 because macrophages from a mouse atherosclerosis model that lacked p62, accumulated ubiquitinated proteins in a diffuse cytoplasmic pattern rather than in discrete vesicles. Mice that were p62-deficient formed greater numbers of more complex atherosclerotic plaques than control mice, and p62 deficiency further increased the atherosclerotic plaque burden in mice that lacked ATG5 in their macrophages.

"That p62 sequesters waste in brain cells was known, and its buildup is a marker for a dysfunctional waste-disposal system," said senior author Dr. Babak Razani, assistant professor of medicine at the Washington University School of Medicine. "But this is the first evidence that its function in macrophages is playing a role in atherosclerosis. If p62 is missing, the proteins do not aggregate. It is tempting to think this might be good for the cell, but we showed this is actually worse. It causes more damage than if the waste were corralled into a large "trash bin." You can imagine a situation where lots of trash is being generated and see that it would be better to keep it all in one place, rather than have it strewn across the floor. You might have difficulty removing the trash to the dumpster, but at least it is contained."

This study was published in the January 5, 2016, online edition of the journal Science Signaling.

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