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Researchers at the University
of Pennsylvania School of Medicine recently identified
how a regulatory protein called Bcl-3 helps to control
the body’s inflammation response to infection by
interfering a critical biochemical process called ubiquitination. |
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Ubiquitination is an intracellular system
of checks and balances, where cellular proteins are flagged
for disposal. During exposure to infection, Bcl-3 appears
to overrule the p50 ubiquitination, stabilizing the presence
of p50 on DNA and halting inflammation. |
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The paper was recently published
in Science. |
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine recently identified how a regulatory protein called Bcl-3 helps to control the body’s inflammation response
to infection by interfering a critical biochemical process called
ubiquitination. While previous studies suggested Bcl-3 plays a
role in immunity, this is the first report that Bcl-3 regulates
inflammation by blocking ubiquitination.
Their findings, published in Science, open new avenues of exploration
for developing therapies to treat infectious or inflammatory diseases,
such as sepsis, diabetes, and rheumatoid
arthritis.
“The novelty of our study is the discovery that Bcl-3 acting on
gene expression has a profound effect on inflammation,” says Ruaidhri
Carmody, PhD, Senior Research Investigator in the Department
of Pathology and Laboratory Medicine and first author of the Science paper. “By
mimicking Bcl-3 activity, we may be able to create an artificial
way to block the inflammatory response.”
In the laboratory of senior author Youhai Chen,
PhD, Associate Professor
of Pathology and Laboratory Medicine, Carmody and others searched for
clues as to how Bcl-3 controls inflammation by examining how Bcl-3-deficient
mouse cells respond to infection. Their studies revealed that Bcl-3 interacts
with p50, a protein that inhibits gene transcription by binding to DNA.
“p50 turns off the DNA region coding for inflammation, halting
the response to infection,” explains Chen. Without Bcl-3, Chen
says p50 cannot stop the inflammation response, but instead will become
degraded very fast, through ubiquintination.
Ubiquitination is an intracellular system of checks and balances, where
cellular proteins are flagged for disposal. During exposure to infection,
Bcl-3 appears to overrule the p50 ubiquitination, stabilizing the presence
of p50 on DNA and halting inflammation.
“Our study identifies another layer of information that controls
the inflammatory response,” says Chen. “Bcl-3 appears to
take in information from the body and, in response to infection, interferes
with p50 degradation to decrease inflammatory response.”
“Inflammation is natural,” says Chen. “If we didn’t
respond to infectious agents, bacteria would kill us. However, the inflammatory
response must be controlled or we could also die. Bcl-3 helps regulate
inflammation.”
“By using what we now know about Bcl-3 regulatory function, we
hope to create new ways to control inflammation for therapeutic purposes
with selective anti-inflammatory agents,” says Carmody.
Although drugs to suppress inflammation currently exist, Chen and Carmody
say they cause many undesirable side effects in patients with inflammatory
diseases.
“Current drug treatments target inflammation signaling pathways.
When you inhibit entire pathways, you can produce negative side effects,” said
Carmody. “Since Bcl-3 acts on specific genes, we should be able
to target a subset of dangerous regulatory genes without disrupting other
important immune responses.” Such drugs could benefit patients
with chronic inflammation and transplant recipients as well as those
suffering with inflammatory diseases.
In the future, the scientists aim to determine the components of the
cell responsible for flagging p50 for destruction and instructing Bcl-3
to perform its vital function.
Penn co-authors are Qingguo
Ruan, Scott Palmer, and Brendan Hilliard.
This research was funded by the National
Institute of Allergy and Infectious Diseases.
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