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

Publication ,  Journal Article
Delorme-Axford, E; Morosky, S; Bomberger, J; Stolz, DB; Jackson, WT; Coyne, CB
Published in: mBio
December 9, 2014

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.

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Published In

mBio

DOI

EISSN

2150-7511

Publication Date

December 9, 2014

Volume

5

Issue

6

Start / End Page

e02147

Location

United States

Related Subject Headings

  • Virus Replication
  • Humans
  • Host-Pathogen Interactions
  • Gene Silencing
  • Gene Expression
  • Enterovirus B, Human
  • Endoplasmic Reticulum
  • Cell Line
  • Carrier Proteins
  • Autophagy
 

Citation

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Delorme-Axford, E., Morosky, S., Bomberger, J., Stolz, D. B., Jackson, W. T., & Coyne, C. B. (2014). BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery. MBio, 5(6), e02147. https://doi.org/10.1128/mBio.02147-14
Delorme-Axford, Elizabeth, Stefanie Morosky, Jennifer Bomberger, Donna B. Stolz, William T. Jackson, and Carolyn B. Coyne. “BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery.MBio 5, no. 6 (December 9, 2014): e02147. https://doi.org/10.1128/mBio.02147-14.
Delorme-Axford E, Morosky S, Bomberger J, Stolz DB, Jackson WT, Coyne CB. BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery. mBio. 2014 Dec 9;5(6):e02147.
Delorme-Axford, Elizabeth, et al. “BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery.MBio, vol. 5, no. 6, Dec. 2014, p. e02147. Pubmed, doi:10.1128/mBio.02147-14.
Delorme-Axford E, Morosky S, Bomberger J, Stolz DB, Jackson WT, Coyne CB. BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery. mBio. 2014 Dec 9;5(6):e02147.

Published In

mBio

DOI

EISSN

2150-7511

Publication Date

December 9, 2014

Volume

5

Issue

6

Start / End Page

e02147

Location

United States

Related Subject Headings

  • Virus Replication
  • Humans
  • Host-Pathogen Interactions
  • Gene Silencing
  • Gene Expression
  • Enterovirus B, Human
  • Endoplasmic Reticulum
  • Cell Line
  • Carrier Proteins
  • Autophagy