Cell-to-cell communication by exosomes controls normal and pathogenic
processes
1
,
2
. Viruses can spread in exosomes and
thereby avoid immune recognition
3
. While biogenesis, binding, and uptake of exosomes are
well-characterized
4
,
5
, delivery of exosome cargo into
the cytoplasm is poorly understood
3
. We report that phosphatidylserine receptor HAVCR1
6
,
7
and cholesterol transporter NPC1
8
participate in cargo delivery from
exosomes of hepatitis A virus (HAV)-infected cells (exo-HAV) by
clathrin-mediated endocytosis. Using CRISPR/Cas9 knockouts we show that these
two lipid receptors, which interact in the late endosome
9
, are necessary for membrane fusion and
delivery of RNA from exo-HAVs into the cytoplasm. The HAVCR1/NPC1 pathway, which
Ebola virus exploits to infect cells
9
, mediates HAV infection by exo-HAV indicating that viral
infection by this exosome mimicry mechanism does not require an envelope
glycoprotein. The luminal viral RNA but not endosomal uncoating of HAV particles
(vpHAV) contained in the exosome is mainly responsible for exo-HAV infectivity
as assessed by methylene blue-inactivation of non-encapsidated RNA. In contrast,
infectivity of vpHAV is pH-independent and requires HAVCR1 or other yet
unidentified receptor(s) but not NPC1. Our findings show that envelope
glycoprotein-independent fusion mechanisms are shared by exosomes and viruses,
and call for a reassessment of the role of envelope glycoproteins in
infection.
Background: Rev7 encodes a subunit of Pol for translesion DNA synthesis (TLS). Results: We found a Rev7 mutation in mice that causes developmental defects and increases susceptibility for genotoxicity. Conclusion: Rev7 is essential for mouse development through its function in cell proliferation.Significance: These findings demonstrate a unique function of Pol in development that is absent in other TLS polymerases.
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