'We're not all that different': Study IDs bacterial weapons that could
be harnessed to treat human disease
Discovery of ancient immune-fighting machinery paves way toward more 'CRISPR'-like technologies

Date:
February 8, 2023
Source:
University of Colorado at Boulder
Summary:
When it comes to fighting off invaders, bacteria operate in a
remarkably similar way to human cells, possessing the same core
machinery required to switch immune pathways on and off, according
to new research.


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FULL STORY ==========================================================================
When it comes to fighting off invaders, bacteria operate in a remarkably similar way to human cells, possessing the same core machinery required
to switch immune pathways on and off, according to new University of
Colorado Boulder research.


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The study, published Feb. 8 in the journal Nature, also sheds light
on how that shared, ancient machinery -- a cluster of enzymes known as ubiquitin transferases -- works.

Better understanding, and potentially reprogramming this machine,
could ultimately pave the way to novel approaches for treating a host of
human diseases, from autoimmune disorders like Rheumatoid arthritis and
Crohn's disease to neurodegenerative diseases like Parkinson's disease,
the authors said.

"This study demonstrates that we're not all that different from bacteria,"
said senior author Aaron Whiteley, an assistant professor in the
Department of Biochemistry. "We can learn a lot about how the human body
works by studying these bacterial processes." The next CRISPR? The study
is not the first to showcase the lessons bacteria can teach humans.

Mounting evidence suggests that portions of the human immune system
may have originated in bacteria, with evolution yielding more complex iterations of bacterial virus-fighting tools across plant and animal
kingdoms.

In 2020, University of California Berkeley biochemist Jennifer Doudna
won the Nobel Prize for CRISPR, a gene-editing tool that repurposes
another obscure system bacteria use to fight off their own viruses,
known as phages.

The buzz around CRISPR ignited renewed scientific interest in the role
proteins and enzymes play in anti-phage immune response.

"Over the past three to five years people have realized it doesn't end
with CRISPR. The potential is so much bigger," said Whiteley.

Missing link in evolutionary history For the study, Whiteley and
co-first author Hannah Ledvina, a Jane Coffin Childs Postdoctoral
Fellow in the department, collaborated with University of California
San Diego biochemists to learn more about a protein called cGAS (cyclic
GMP-AMP synthase), previously shown to be present in both humans and,
in a simpler form, bacteria.

In bacteria and in humans, cGAS is critical for mounting a downstream
defense when the cell senses a viral invader. But what regulates this
process in bacteria was previously unknown.

Using an ultra-high-resolution technique called cryo-electron microscopy alongside other genetic and biochemical experiments, Whiteley's team took
an up-close look at the structure of cGAS's evolutionary predecessor in bacteria and discovered additional proteins that bacteria use to help
cGAS defend the cell from viral attack.

Specifically, they discovered that bacteria modify their cGAS using a streamlined "all-in-one version" of ubiquitin transferase, a complex
collection of enzymes that in humans control immune signaling and other critical cellular processes.

Because bacteria are easier to genetically manipulate and study than
human cells, this discovery opens a new world of opportunity for research,
said Ledvina.

"The ubiquitin transferases in bacteria are a missing link in our
understanding of the evolutionary history of these proteins." Editing
proteins The study also revealed just how this machine works, identifying
two key components -- proteins called Cap2 and Cap3 (CD-NTase-associated protein 2 and 3) -- which serve, respectively, as on and off switches
for the cGAS response.

Whiteley explained that in addition to playing a key role in immune
response, ubiquitin in humans can serve as a sort of marker for
cellular garbage, directing excess or old proteins to be broken down and destroyed. When that system misfires due to mutations in the machine,
proteins can build up and diseases, such as Parkinson's, can occur.

The authors stress that far more research is needed but the discovery
opens exciting scientific doors. Just as scientists adapted the ancient bacterial defense system CRISPR into scissor-like biotechnology that
can snip mutations out of DNA, Whiteley believes pieces of the bacterial ubiquitin transferase machine -- namely Cap3, the "off switch" -- could ultimately be programmed to edit out problem proteins and treat disease
in humans.

He and his team, with the help of Venture Partners at CU Boulder, have
already filed for intellectual property protection, and they're moving
forward with more research.

"The more we understand about ubiquitin transferases and how they evolved,
the better equipped the scientific community is to target these proteins therapeutically,"Whiteley said. "This study provides really clear evidence
that the machines in our body that are important for just maintaining
the cell started out in bacteria doing some really exciting things."
* RELATED_TOPICS
o Health_&_Medicine
# Human_Biology # Immune_System # Infectious_Diseases
# Lymphoma
o Plants_&_Animals
# Bacteria # CRISPR_Gene_Editing #
Biotechnology_and_Bioengineering # Biology
* RELATED_TERMS
o Immune_system o Great_Ape_language o Pathogen o T_cell o
HIV o Transplant_rejection o Adult_stem_cell o White_blood_cell

========================================================================== Story Source: Materials provided by
University_of_Colorado_at_Boulder. Original written by Lisa
Marshall. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hannah E. Ledvina, Qiaozhen Ye, Yajie Gu, Ashley E. Sullivan,
Yun Quan,
Rebecca K. Lau, Huilin Zhou, Kevin D. Corbett, Aaron T. Whiteley. An
E1- E2 fusion protein primes antiviral immune signalling in
bacteria. Nature, 2023; DOI: 10.1038/s41586-022-05647-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/02/230208191716.htm

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