Form is (mal)function: Protein's shape lets bacteria disarm it
Researchers show a crucial protein of the innate immune system has six different forms, and probably many different roles in the body
Date:
March 30, 2023
Source:
University of Connecticut
Summary:
Shigella bacteria can infect humans but not mice. A team can now
explain why. Their findings may explain the multifariousness of
a key weapon of our immune system.
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FULL STORY ========================================================================== Shigella bacteria can infect humans but not mice. In the March 29 issue ofNature, a team from UConn Health explains why. Their findings may
explain the multifariousness of a key weapon of our immune system.
========================================================================== Shigella infections cause fever, stomach pain, and prolonged, sometimes
bloody diarrhea for as long as a week. The bacteria sicken 450,000
people each year in the US alone. Although most people recover on their
own, children and those with weakened immune systems are at risk of
Shigella infections spreading to their bloodstream and causing kidney
damage. Shigella infections are a significant cause of sickness and
disability, but it's difficult to study the bacteria because it only
sickens primates like humans and apes -- not animals easy to study in
a lab. The bacteria cannot infect more typical lab animals such as mice.
Previous research had looked at how Shigella interacts with gasdermin-B,
a critical part of our immune system that helps protect us against
infection.
Gasdermin-B is member of a protein family called gasdermin, which includes gasdermin-A, -B, -C, -D, -E and -F. It was thought that when gasdermin-
B detects an invader, such as bacteria, it begins to poke holes in the
cell's wall, causing it to burst open and release chemicals that induce inflammation and call reinforcements from the immune system. But the
past research studies on gasdermin-B were contradictory; some confirmed
its role in cell death during infection, but others contradicted the idea.
UConn School of Medicine immunologist Jianbin Ruan and a team of
colleagues from UConn Health wanted to clarify whether gasdermin-B
actually does cause cell death in the case of microbial invasion;
they also wanted to figure out why it doesn't do this when Shigella is
the invader.
The team needed to take a close look at gasdermin-B. They expressed
the protein, purified it, and then cooled the protein down to very low temperatures so it would hold still while they took pictures of it with
an electron microscope.
"We collected hundreds of thousands of images to build the 3D models
of protein molecules at the atomic level. Through these models we will understand what these proteins look like and how they do their job,"
said Chengliang Wang, research fellow in the Ruan lab and first author
of the study.
Their research confirms previous research and provides evidence
that Shigella bacteria grab onto a specific segment of gasdermin-B in
humans. However, the mouse version of the protein has a different shape
that prevents Shigella from latching onto it, resulting in the rapid
clearance of the bacteria and preventing infection. This finding helps
explain why Shigella is unable to infect mice.
Since human gasdermin-B can be configured in six slightly differing
proteins, or isoforms, the team expressed all six then looked at how
these isoforms behaved inside cells, and they found something surprising:
some of the isoforms of gasdermin-B did indeed poke holes to cause cell
death -- but other isoforms did not.
"Previously, people didn't understand why studies contradicted each
other. We show that only two of the isoforms of gasdermin-B cause
pyroptosis, or cell death," says Ruan. Those two isoforms contain a
specific protein segment that is absent in the other gasdermin-B isoforms,
as shown by their cryogenic electron microscopy structure.
The finding may explain many mysteries of cell death, and life. Cancer
cells, for example, are notoriously long lived and unlikely to die via pyroptosis. It may be that these cancer cells express only gasdermin-B
isoforms that don't poke holes in cell walls.
However, we don't yet know what these other isoforms are doing. It
may be that the different isoforms of gasdermin-B play significant and distinctive roles depending on where they are in the body, and different
cell types preferentially express different isoforms.
"The protein structures that our team discovered have significant
implications for drug development. Specifically, they can inform the
design of small molecule drugs that modulate gasdermin-B activity,"
explains Ruan. "These drugs could potentially be used to treat a range
of conditions, including cancer, inflammatory and autoimmune diseases,
and infectious diseases by either suppressing or enhancing the immune
response. Our findings thus hold promise for the development of novel
therapies to address these pressing medical needs."
* RELATED_TOPICS
o Health_&_Medicine
# Immune_System # Lymphoma # Diseases_and_Conditions #
Human_Biology
o Plants_&_Animals
# Molecular_Biology # Cell_Biology # Biotechnology #
Biotechnology_and_Bioengineering
* RELATED_TERMS
o Immune_system o Transplant_rejection o House_mouse o Pathogen
o Visual_perception o Biological_warfare o Mouse o Lymphoma
========================================================================== Story Source: Materials provided by University_of_Connecticut. Original
written by Kim Krieger. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Chengliang Wang, Sonia Shivcharan, Tian Tian, Skylar Wright,
Danyang Ma,
JengYih Chang, Kunpeng Li, Kangkang Song, Chen Xu, Vijay
A. Rathinam, Jianbin Ruan. Structural basis for GSDMB pore
formation and its targeting by IpaH7.8. Nature, 2023; DOI:
10.1038/s41586-023-05832-z ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2023/03/230330172215.htm
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