title: BPIFB3 regulates autophagy and coxsackievirus B replication through a noncanonical pathway independent of the core initiation machinery.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Delorme-Axford
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Morosky
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bomberger
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Jackson
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA coynec2@pitt.edu.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
mesh_terms: D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000737:chemistry; D029822:Enterovirus B, Human / Q000502:physiology*; D015870:Gene Expression; D020868:Gene Silencing; D054884:Host-Pathogen Interactions; D006801:Humans; D014779:Virus Replication
chemical_list: C000598890:BPIFB3 protein, human; D002352:Carrier Proteins