Sensor spies hideouts for ?virus replication
An antiviral, found in some people's cells, outwits an immune escape plan
used by several dangerous viruses

Date:
August 13, 2021
Source:
University of Washington School of Medicine/UW Medicine
Summary:
Some types of RNA viruses cloak themselves to hide inside a cell
and create copies of themselves. But an enzyme that acts as a virus
sensor might be attuned to their whereabouts. A slight variation
in their genomic code gives some people's cells the capacity to
produce this sensor. Researchers discovered how this sensor helps
cells stop the virus before it multiplies too greatly.



FULL STORY ========================================================================== While some types of RNA viruses cloak themselves to hide inside a cell
and create copies of themselves, a "detective enzyme" might be attuned
to their whereabouts. A slight variation in their genomic code gives
some people's cells the capacity to produce this sensor.


==========================================================================
Many positive-strand RNA viruses share a strategy to avoid detection by
a cell's immune system until they can increase their numbers. Among them
are the SARS-CoV-2 virus, flaviviruses such as West Nile and Zika, as well
as the picornaviruses behind polio and some heart and brain inflammation.

After invading a cell, these types of viruses take over part of an intracellular membrane, within the system of membranes that form
compartments within the cell. The viruses use this modified organelle
as a refuge for replicating themselves. Their viral products are thereby shielded from most of the cell's innate immune sensors.

A new study looks at how a variant of the enzyme, oligoadenylate
synthetase 1, targets the hiding spots of these viruses. This isoform of
the enzyme is called OAS1 p46. The OAS family of sensors are prompted by interferon to seek out RNA viruses or their locations. This reconnaissance helps the cell defend against the attack.

Although much research has documented the importance of OAS proteins in activating an enzyme that cleaves viral RNA in order to block a variety of different viruses from replicating, little is known about how individual
OAS proteins contribute to this breadth of antiviral activity.

Most of a cell's RNA virus sensors are deployed to detect viruses
within the cytosol that is between the nucleus and the outer membrane
of the cell. They sense viral RNA that accumulates in the cytosol during infection.



==========================================================================
In contrast, the OAS1 p46 protein isoform homes in on the endomembrane
system, particularly the endoplasmic reticulum and the Golgi
apparatus. The Golgi is a cellular mailing room where proteins are
packaged and dispatched.

The OAS1 p46 isoform is also prenylated, a biochemical tune up
that, in this case, gives this protein the ability to traffic to the
membranes. This isoform also has additional help from amino acids at
the tail end of the protein that also improves its antiviral activity.

"Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments
for replication," the researchers noted in their paper, which appears
in eLife.

The senior author of the paper is Ram Savan, an associate professor
of immunology at the University of Washington School of Medicine in
Seattle. His lab explores how variations in, and regulation of, innate
immunity genes help determine resistance or susceptibility to serious
viral infections that affects us.

The lead authors on the international, multi-institutional study are
Frank W.

Soveg, a recent graduate student in the Ram Savan Lab and Johannes
Schwerk, acting instructor in immunology at the UW School of Medicine. All three are also members of the UW Center for Innate Immunity and Immune
Disease.



==========================================================================
The authors found that the OAS1 p46 isoform's localization to these
membranes enhances the cell's virus sensors access the viral replication
sites. This in turn results in a stronger antiviral activity against the
sorts of RNA viruses that tend to use this hiding-in-a-membrane tactic
to covertly multiply.

"Our virological analysis," Ram Savan observed, "shows that OAS1 p46
isoform is pan-antiviral against multiple positive-strand RNA viruses
including flavivirus, picornavirus and SARS-CoV-2." The scientists went
on to analyze the human genetics behind the OAS1 p46 isoform, and the
benefits of having this genetic variant, by examining lab samples from
patients affected by COVID-19.

"In this study," Ram Savan noted, "we identify a causal single
nucleotide variant in the oligoadenylate synthetase 1 gene that predicts COVID-19 severity." Savan explained that the genetic data show a
strong association of the A allele that produces the OAS1 p42 protein
isoform with severe COVID-19 disease requiring mechanical ventilation
of patients. On the other hand, the G allele producing OAS1p46 protein
protects from severe COVID-19. The results from patients in the Pacific Northwest were reproduced in a larger European cohort.

In summary, the scientists noted that their findings show that targeting endomembranes is vital for the antiviral action of OAS1 against specific
types of immunity-evading pathogens. The work demonstrates how critical
such intracellular membrane targeting is in detecting dangerous viruses
that replicate on these membranes. The results also suggest that the
control of SARS-CoV-2 replication early on in infection, through the
actions of the OAS1- p46 isoform, is an important factor in reducing
the severity of COVID-19 disease.

This project was funded by National Institutes of Health (grants AI145974, AI108765, AI135437, AI104002, AI118916, AI145296, AI127463, AI100625,
AI106677, GM007270, and AI140530; T32 HL007312); Postdoctoral Research Fellowship from the German Research Foundation and support from the
Cancer Research Institute Irvington Fellowship Program.

========================================================================== Story Source: Materials provided by University_of_Washington_School_of_Medicine/UW_Medicine.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Frank W Soveg, Johannes Schwerk, Nandan S Gokhale, Karen
Cerosaletti,
Julian R Smith, Erola Pairo-Castineira, Alison M Kell, Adriana
Forero, Shivam A Zaver, Katharina Esser-Nobis, Justin A Roby,
Tien-Ying Hsiang, Snehal Ozarkar, Jonathan M Clingan, Eileen
T McAnarney, Amy EL Stone, Uma Malhotra, Cate Speake, Joseph
Perez, Chiraag Balu, Eric J Allenspach, Jennifer L Hyde, Vineet
D Menachery, Saumendra N Sarkar, Joshua J Woodward, Daniel B
Stetson, John Kenneth Baillie, Jane H Buckner, Michael Gale, Ram
Savan. Endomembrane targeting of human OAS1 p46 augments antiviral
activity. eLife, 2021; 10 DOI: 10.7554/eLife.71047 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210813180706.htm

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