In the blood and other circulating fluids, proteins stay on the job only as long as they can maintain a youthful appearance. When proteins start showing the equivalent of gray around the temples—degraded N-glycan linkages—they are soon ushered out of the proteomic workforce, however able-bodied they might be.
This finding, which appeared October 21 in the Proceedings of the National Academy of Sciences (PNAS), suggests that it might be possible to extend the working lives of proteins, or force proteins into early retirement—adjusting the composition of the proteomic workforce to promote health while sidelining or terminating disease processes.
The aging and turnover of secreted proteins, it turns out, encompasses multiple factors, including circulating enzymes called glycosidases. These enzymes progressively remodel N-glycans, which are complex structures of monosaccharide sugars linked together and attached to virtually all secreted proteins.
Over time, sugar linkage by sugar linkage, the N-glycans that initially grace proteins lose their sheen and become increasingly coarse. Then the proteins run afoul of endocytic lectins, which are carbohydrate-binding receptors. Essentially, these lectins recognize aged proteins and eliminate them from circulation.
Details of this protein-culling process were uncovered by scientists at the University of California, Santa Barbara (UCSB) and the Sanford-Burnham-Prebys (SBP) Medical Discovery Institute. These scientists, led by Jamey Marth, Ph.D., a researcher affiliated with both institutions, summarized their results in the PNAS paper, which was entitled, “An intrinsic mechanism of secreted protein aging and turnover.”
“Endogenous glycosidases, including neuraminidase 1 (Neu1), neuraminidase 3 (Neu3), beta-galactosidase 1 (Glb1), and hexosaminidase B (HexB), possess hydrolytic activities that temporally remodel N-glycan structures, progressively exposing different saccharides with increased protein age,” the article’s authors wrote. “Subsequently, endocytic lectins with distinct binding specificities, including the Ashwell–Morell receptor, integrin αM, and macrophage mannose receptor, are engaged in N-glycan ligand recognition and the turnover of secreted proteins.”
The authors also noted that glycosidase inhibition and lectin deficiencies could increase protein life spans and abundance. Finally, they determined that the basal rate of N-glycan remodeling varied among distinct proteins, accounting for differences in their life spans.
“When a secreted protein is made, it has a useful life span and then it must be degraded—the components are then basically recycled,” said Dr. Marth. “We can now see how the regulation and alteration of secreted protein aging and turnover is able to change the composition of the circulatory system and thereby maintain health as well as contribute to various diseases.”
“The discovery of this mechanism provides a unique window into disease origins and progression,” Dr. Marth continued. “It has been known that circulating glycosidase enzyme levels are altered in diseases such as sepsis, diabetes, cancer, and various inflammatory conditions. The resulting changes in the composition and function of the circulatory systems, including the blood and the lymphatic systems, can now be identified and studied. We are beginning to see previously unknown molecular pathways and connections in the onset and progression of disease.”
Dr. Marth added that altering the protein aging and turnover mechanism “is the fastest way to change the abundance of a secreted protein,” a quantity that is increasingly recognized as having significance at the interface of health and disease.