Uncovering Albumin’s Role in Fertility and Inflammation

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Researchers have discovered that albumin (Alb), one of the most abundant proteins in the body, activates a proton channel (hHv1), also widespread in the body, giving sperm the ability to penetrate and fertilise an egg, and also allowing white blood cells to produce inflammatory mediators to fight infection.

The study explored the physiological connection between Alb and human voltage-gated proton channels (hHv1), which are both essential to cell biology in health and diseases. Researchers also demonstrated the mechanism by which Alb binds directly to hHv1 to activate the channel. This research explains how sperm are triggered to fertilise, and neutrophils are stimulated to release mediators in the innate immune response, describing a new role for Alb in physiology that will operate in the many tissues expressing hHv1.

“We found that the interaction of Alb and hHv1 activates sperm when they leave semen and enter the female reproductive tract because Alb is low in semen and high in the reproductive tract. We now understand why albumin supplementation improves IVF,” explained first author Ruiming Zhao, PhD, from the Department of Physiology & Biophysics at UCI School of Medicine. “We also found the same Alb/hHv1 interaction allows the white blood cells called neutrophils to produce and secrete the inflammatory mediators that kill bacteria and fight infection. However, it’s important to note that the inflammatory response itself can lead to disease.”

Alb’s stimulating role in the physiology of sperm and neutrophils via hHv1 pointed to its having other enhancing or deleterious roles in the other tissues, including the central nervous system, heart and lungs, and influencing cancers of the breast and gastrointestinal tract.

“It is exciting to discover that a common protein has the power to activate the proton channel.  This finding suggests new strategies to block or enhance fertility, and to augment or suppress the innate immune response and inflammation,” said senior author Steve A. N. Goldstein, MD, PhD, vice chancellor of Health Affairs at UCI.

hHv1 is involved in many biological processes in addition to the capacitation of sperm and the innate immune responses included in the study.  The channels have notable roles in proliferation of cancer cells, tissue damage during ischaemic stroke, and hypertensive kidney injury. Because Alb’s presence and involvement varies, the potentiation of hHv1 by Alb can be either beneficial or detrimental in different diseases or conditions.

“We have modeled the structural basis for binding of Alb to the channel that leads to activation and changes in cellular function, and we are now conducting in vivo studies of viral and bacterial infections.  Our next steps include studies of the effects of inhibitors of the Alb-hHv1 interaction on infection, inflammation and fertility,” said Goldstein.  

Source: University of California, Irvine

Journal information: Ruiming Zhao et al, Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils, Nature Communications (2021). DOI: 10.1038/s41467-021-24145-1

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