Human immune system uses ancient family of cell death proteins also
found in bacteria
Study illustrates conservation of immune system's cell death mechanisms originating billions of years ago in single-celled organisms.

Date:
January 13, 2022
Source:
Dana-Farber Cancer Institute
Summary:
The human immune system, that marvel of complexity, subtlety,
and sophistication, includes a billion-year-old family of proteins
used by bacteria to defend themselves against viruses, scientists
have discovered.



FULL STORY ==========================================================================
The human immune system, that marvel of complexity, subtlety, and sophistication, includes a billion-year-old family of proteins used by
bacteria to defend themselves against viruses, scientists at Dana-Farber
Cancer Institute and in Israel have discovered.


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The findings, published online today by the journal Science, are the
latest in a growing body of evidence that components of our immune
system -- as advanced a shield against disease as exists on the planet -- evolved early in ancient forms of life. The study shows that the immune
system absorbed already existing elements and, over eons of evolution,
put them to use in novel ways to meet the requirements of creatures as biologically complicated as human beings.

"There has been a tremendous amount of work by researchers around
the world to understand how the human immune system functions," says
the study's senior author, Philip Kranzusch, PhD, of Dana-Farber. "The discovery that key parts of human immunity are shared in bacteria provides
a new blueprint for research in this area." The proteins at the center
of the study are known as gasdermins. When a cell becomes infected or
turns cancerous, gasdermins form pores that punch holes in its membrane, causing it to die. Substances known as inflammatory cytokines leak from
the holes, signaling the presence of infection or cancer and prompting
the immune system to rally to the body's defense.

This process, called pyroptosis, is one facet of the immune system's
repertoire for killing diseased or infected cells. It complements the better-known process of apoptosis, in which crippled or infected cells self-destruct after being damaged. "Pyroptosis represents one of the
fastest ways that the innate immune system [the body's first line of
defense against pathogens] responds to potential threats," says the new
study's co-first author, Alex Johnson, PhD, of Dana-Farber.

The human genome holds the code for six gasdermin proteins, which are
expressed at varying levels in different cell types. For the current
study, Johnson and his colleagues explored whether the ancestors of any
of these proteins existed in bacteria.



==========================================================================
They had good reason for thinking they might. In 2019, Kranzusch and his colleagues found that a human immune signaling pathway called cGAS-STING,
which senses abnormalities linked to cancer and infection, originated
in bacteria.

"This and other discoveries motivated us to look for additional
connections between immune-related proteins in human and bacterial cells," Kranzusch notes.

Co-first author Tanita Wein, PhD, co-senior author Rotem Sorek, PhD,
and colleagues at the Weizmann Institute of Science, in Israel, analyzed sections of bacterial DNA known as "antiphage defense islands" because
they contain clusters of genes that protect bacteria from infection by
viruses known as phages. They identified 50 bacterial genes predicted to
give rise to proteins whose structure was similar to that of gasdermin
proteins in mammals.

"I determined a series of structures of these proteins using X-ray crystallography, which confirmed at atomic detail their architectural similarity with mammalian gasdermins," Johnson relates. The types of
bacteria that harbor these proteins are widespread, living in soil,
leaves, and other natural habitats. (The particular bacterium most studied
in Johnson's research was first identified on a corn plant in Wisconsin.) Johnson's structural work showed that while human and bacterial gasdermins
are structurally alike, the bacterial versions tend to be about half as
big, yet serve as building blocks for membrane pores larger than those
seen in humans.

All these gasdermins are activated by a similar mechanism, but the chain
of events they set in motion is far more extensive in human cells. In
bacterial cells, viral infection may trigger cells to die from punctured membranes, stopping viruses in their tracks. In human cells, the death of
an infected cell triggers a cascade of events that brings other elements
of the immune system to bear on the infection.

"This is an example of a very primitive form of defense, which, in humans,
has been adapted and expanded with regulatory systems that enable our
bodies to respond to infection or cancer," Kranzusch says.

The discovery of traces of a primitive form of immunity within the
staggering complexity of the human immune system can help researchers
better understand how the system came to be. "Seeing the simplest version
of a machine can give you a new level of understanding of the machine
as a whole," Kranzusch remarks.

"The same principle can apply to research into the immune system."
Co-authors of the study are: Brianna Duncan-Lowey, PhD, of Dana-Farber;
Megan Mayer, MS, of the Harvard Center for Cryo-Electron Microscopy;
and Erez Yimiya, Yaara Oppenheimer-Shaanan, PhD, and Gil Amitai, PhD,
of the Weizmann Institute.

Funding for the study was provided by: the Pew Biomedical Scholars
Program; the Burroughs Wellcome Fund; the Mathers Foundation; the Parker Institute for Cancer Immunotherapy; the European Research Council;
the Israel Science Foundation; the Ernest and Bonnie Beutler Research
Program of Excellence; the Minerva Foundation and Federal German Ministry
for Education and Research; the Knell Family Center for Microbiology;
the Yotam project and the Weizmann Institute Sustainability and Energy
Research Initiative; the Dr. Barry Sherman Institute for Medicinal
Chemistry; the National Institute of Health Cancer Immunology (training
grant T32CA207021); a Life Science Research Foundation postdoctoral
fellowship of the Open Philanthropy Project; a Minerva Foundation
postdoctoral fellowship; and a Herchel Smith Graduate Research Fellowship.

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


========================================================================== Journal Reference:
1. Alex G. Johnson et al. Bacterial gasdermins reveal an ancient
mechanism
of cell death. Science, 2022 DOI: 10.1126/science.abj8432 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220113151339.htm
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