Research advances knowledge of the battle between viruses and human
cells
Discovery of protective RNA mechanism informs pursuit to develop anti-
viral drugs

Date:
February 18, 2022
Source:
University of Massachusetts Amherst
Summary:
In the long-term battle between a herpesvirus and its human host,
a virologist and her team of students have identified some human
RNA able to resist the viral takeover -- and the mechanism by
which that occurs.



FULL STORY ==========================================================================
In the long-term battle between a herpesvirus and its human host, a
University of Massachusetts virologist and her team of students have
identified some human RNA able to resist the viral takeover -- and the mechanism by which that occurs.


==========================================================================
This discovery, described in a paper published Feb. 15 inProceedings of
the National Academy of Sciences, represents an important step in the
effort to develop anti-viral drugs to fight off infections.

"This paper is about trying to understand the mechanism that makes these
RNA escape degradation," says senior author Mandy Muller, assistant
professor of microbiology. "The next step is to figure out if we can
manipulate this to our advantage." In the Muller Lab, student researchers
work with Muller studying how Kaposi sarcoma-associated herpesvirus (KSHV) hides for years inside the human body before seeking to gain control over
human gene expression to complete the viral infection. At that point,
people with a weakened immune system may develop Kaposi sarcoma cancer
lesions in the mouth, skin or other organs.

The researchers use genome-wide sequencing, post-transcriptional
sequencing and molecular biology to examine how the human cell or the
virus knows how to prevent degradation.

"Viruses are very smart, that's what I love to say," Muller says. "They
have lots of strategies to stick around, and they don't do a lot of
damage for a very long time, because that's one way to hide from the
immune system.



==========================================================================
"But then, at some point -- many, many years later -- they reactivate. The
way they do this is by triggering a massive RNA degradation event where
the virus will wipe out the mRNA from the cell. That means the human
system can no longer express the proteins that it needs to express,
and that means also that a lot of resources are suddenly available for
the virus." How and why some RNA are able to escape the viral degradation
are questions Muller's team -- including lead author and graduate student Daniel Macveigh- Fierro and co-authors and undergraduates Angelina
Cicerchia, Ashley Cadorette and Vasudha Sharma -- has been investigating.

"We show that RNA that escape have a chemical tag on them -- a post- transcriptional modification -- that makes them different from the
others," Muller explains. "By having this tag, M6A, they can recruit
proteins that protect them from degradation." Muller has been studying
KSHV since she was an undergraduate in her native France, and her
mission continues.

"We know you need this protein to protect the RNA from degradation,
but we still don't know how that physically stops the degradation,
so that's what we're going to look at now," she says.

Ultimately, understanding the mechanisms and pathways involved in KSHV infection may lead to the development of RNA therapeutics to treat
viral diseases.

"By identifying the determinants of what makes an mRNA either resistant
or susceptible to viral-induced decay, we could use those findings to
our advantage to better design anti-viral drugs and reshape the outcome
of infection," Muller says.

The research was supported by a $1.9 million Maximizing Investigators'
Research Award (MIRA) to Muller in 2020 from the NIH's National Institute
for General Medical Sciences.

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


========================================================================== Journal Reference:
1. Daniel Macveigh-Fierro, Angelina Cicerchia, Ashley Cadorette,
Vasudha
Sharma, Mandy Muller. The m6A reader YTHDC2 is essential for escape
from KSHV SOX-induced RNA decay. Proceedings of the National Academy
of Sciences, 2022; 119 (8): e2116662119 DOI: 10.1073/pnas.2116662119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220218153050.htm

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