Immune activation in the liver illuminated with new glycan-tagging
strategy

Date:
October 19, 2020
Source:
Scripps Research Institute
Summary:
A signaling system implicated in liver fibrosis and immune
activation is better understood thanks to this creative chemical
fishing lure.



FULL STORY ========================================================================== Human cells are encased by a membrane coated with diverse sugar molecules
known as glycans. These glycans play many roles in health and disease,
making them important to understand. Due to their unique properties,
however, scientists have had limited tools to study them and their
interactions in the body.


==========================================================================
New research from the lab of biochemist Mia Huang, PhD, an assistant
professor at Scripps Research in Jupiter, Florida, presents a strategy
for capturing elusive interactions among glycans and their protein
activators in live human cells. Huang and her colleagues applied the
technique to improve understanding of liver disease and immune activation.

Writing in the journal the Proceedings of the National Academies
of Sciences on Friday, Huang and colleagues focus on a glycan-binding
protein called galectin- 3. Collaborating with the lab of Scripps Research chemist Chris Parker, PhD, the team was able to catalog galectin-3's
array of receptors by combining two strategies: proximity labelling and quantitative proteomics.

In the process, they discovered hundreds of galectin-3 interactors in
live liver stellate cells and immune cells.

"These interactions escape traditional query because of their weak
affinity and dynamic binding events," Huang says. "Our findings will
empower our ability to approach, and hopefully treat, diseases based on glycosylation-mediated events, especially liver fibrosis and autoimmune disorders." Finding the hook Cells communicate with each other through
the release of molecular signals.

These signals, such as galectin-3, can activate the inflammatory response following viral infection, or generate a buildup of scar tissue following injury, for example.



==========================================================================
At the biochemical level, for this to happen, a glycan-binding protein
must attach to its membrane receptor like a fisherman's line hook wading through thick kelp to find its catch. Characterizing which hooks fit
which glycoproteins is a necessary step to addressing the root causes
of many illnesses, Huang says.

A graduate student in Huang's lab, Eugene Joeh, devised a chemical fishing expedition to search for galectin-3. Joeh, a student in Scripps Research's Skaggs Graduate School of Chemical and Biological Sciences, suggested
tethering an enzyme called APEX2, chosen for its relatively small size and ability to stay active both inside and outside the cell, to the galectin-3 molecules. He then allowed the paired molecules to freely diffuse onto
cells. Next, he added the chemicals biotin phenol and hydrogen peroxide
to create highly reactive tags that label the binding complexes so that
they could be more easily identified and characterized. He was helped
by a participant in the institute's high school internship program,
Kenan Fellow Jonathan Hung, a student at Suncoast High School at the
time of his internship, now a freshman at Johns Hopkins University.

Liver fibrosis and beyond The liver plays many roles. It processes
nutrients and medicines absorbed through digestion. It clears toxins,
breaks down alcohol, and stores or releases fats and sugars during times
of plenty or scarcity. It makes bile to help digest fats. Over time,
injury to the liver from conditions such as alcoholism, autoimmune
disease, drug abuse, or viral hepatitis, can lead to a condition called
liver fibrosis. This can cause chronic high blood pressure, cirrhosis
or even liver failure.

The events that lead to this unhealthy cascade involve an interaction
between liver-based immune white blood cells called macrophages and
fat-storing liver cells called stellate cells. The cascade begins when
liver macrophages activate liver stellate cells through the release of galectin-3. The docking of galectin-3 to its sugary glycoprotein receptors triggers the stellate cell to ooze collagen and make other changes.



==========================================================================
This signal, galectin-3, isn't only a force to consider in liver
fibrosis. It also plays an important role in other cells -- especially
those in the immune system that help defend against infections, cancer
and poisons, Huang says.

"It is noteworthy that several of these proteins are important in both
the innate and adaptive immune responses," Huang says.

The discovery of so many galectin-3 receptors raises many new questions,
she adds. The work continues.

"This has given us a priority list of proteins that will be the subject
of further work on the regulation of immunity and the activation of
liver stellate cells," she says.


========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Eugene Joeh, Timothy O'Leary, Weichao Li, Richard Hawkins,
Jonathan R.

Hung, Christopher G. Parker, Mia L. Huang. Mapping glycan-mediated
galectin-3 interactions by live cell proximity labeling. Proceedings
of the National Academy of Sciences, 2020; 202009206 DOI: 10.1073/
pnas.2009206117 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201019133658.htm

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