BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery.

dc.contributor.author

Delorme-Axford, Elizabeth

dc.contributor.author

Morosky, Stefanie

dc.contributor.author

Bomberger, Jennifer

dc.contributor.author

Stolz, Donna B

dc.contributor.author

Jackson, William T

dc.contributor.author

Coyne, Carolyn B

dc.date.accessioned

2021-04-16T20:03:48Z

dc.date.available

2021-04-16T20:03:48Z

dc.date.issued

2014-12-09

dc.date.updated

2021-04-16T20:03:46Z

dc.description.abstract

Unlabelled

Enteroviruses require autophagy to facilitate the formation of autophagosome (AP)-like double-membrane vesicles that provide the scaffolding for RNA replication. Here, we identify bactericidal/permeability-increasing protein (BPI) fold-containing family B, member 3 (BPIFB3) as a gene whose silencing greatly enhances coxsackievirus B (CVB) replication and induces dramatic alterations in the morphology of CVB-induced replication organelles. We show that BPIFB3 is associated with the endoplasmic reticulum (ER), and its silencing by RNA interference enhances basal levels of autophagy and promotes increased autophagy during CVB replication. Conversely, overexpression of BPIFB3 inhibits CVB replication, dramatically alters the morphology of LC3B-positive vesicles, and suppresses autophagy in response to rapamycin. In addition, we found that, whereas silencing of core autophagy components associated with the initiation of APs in control cells suppressed CVB replication, silencing of these same components had no effect on CVB-induced autophagy or viral replication in cells transfected with BPIFB3 small interfering RNA. Based on these results, taken together, this study reports on a previously uncharacterized regulator of enterovirus infection that controls replication through a noncanonical pathway independent from the core autophagy initiation machinery.

Importance

Coxsackievirus B (CVB) infections are commonly associated with dilated cardiomyopathy, a condition that accounts for nearly half of all heart transplants annually. During infection, CVB co-opts a cellular pathway, termed autophagy, to provide the membranes necessary for its replication. Autophagy is an evolutionarily conserved process by which cells ingest damaged organelles as a means of maintaining cell homeostasis. Here, we report on a novel regulator of autophagy, bactericidal/permeability-increasing protein (BPI) fold-containing family B, member 3 (BPIFB3), whose expression functions to restrict CVB replication by suppressing key steps in the authophagic process. We show that loss of BPIFB3 expression greatly enhances CVB replication while having no effect on replication of poliovirus, a closely related virus. Our results thus identify a novel host cell therapeutic target whose function could be targeted to alter CVB replication.
dc.identifier

mBio.02147-14

dc.identifier.issn

2150-7511

dc.identifier.issn

2150-7511

dc.identifier.uri

https://hdl.handle.net/10161/22595

dc.language

eng

dc.relation.ispartof

mBio

dc.relation.isversionof

10.1128/mbio.02147-14

dc.subject

Cell Line

dc.subject

Endoplasmic Reticulum

dc.subject

Humans

dc.subject

Enterovirus B, Human

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Carrier Proteins

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Virus Replication

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Gene Expression

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Gene Silencing

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Autophagy

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Host-Pathogen Interactions

dc.title

BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery.

dc.type

Journal article

duke.contributor.orcid

Coyne, Carolyn B|0000-0002-1884-6309

pubs.begin-page

e02147

pubs.issue

6

pubs.organisational-group

School of Medicine

pubs.organisational-group

Molecular Genetics and Microbiology

pubs.organisational-group

Duke

pubs.organisational-group

Basic Science Departments

pubs.publication-status

Published

pubs.volume

5

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