BH3-only sensors Bad, Noxa and Puma are Key Regulators of Tacaribe virus-induced Apoptosis.
Apoptosis
Apoptosis Regulatory Proteins
/ genetics
Arenaviridae Infections
/ genetics
Arenaviruses, New World
/ physiology
Gene Expression Regulation
Host-Pathogen Interactions
Humans
Protein Domains
Proto-Oncogene Proteins
/ genetics
Proto-Oncogene Proteins c-bcl-2
/ genetics
Virus Replication
bcl-Associated Death Protein
/ genetics
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
03
06
2020
accepted:
31
08
2020
revised:
30
10
2020
pubmed:
13
10
2020
medline:
5
1
2021
entrez:
12
10
2020
Statut:
epublish
Résumé
Pathogenicity often differs dramatically among even closely related arenavirus species. For instance, Junín virus (JUNV), the causative agent of Argentine hemorrhagic fever (AHF), is closely related to Tacaribe virus (TCRV), which is normally avirulent in humans. While little is known about how host cell pathways are regulated in response to arenavirus infection, or how this contributes to virulence, these two viruses have been found to differ markedly in their ability to induce apoptosis. However, details of the mechanism(s) governing the apoptotic response to arenavirus infections are unknown. Here we confirm that TCRV-induced apoptosis is mitochondria-regulated, with associated canonical hallmarks of the intrinsic apoptotic pathway, and go on to identify the pro- and anti-apoptotic Bcl-2 factors responsible for regulating this process. In particular, levels of the pro-apoptotic BH3-only proteins Noxa and Puma, as well as their canonical transcription factor p53, were strongly increased. Interestingly, TCRV infection also led to the accumulation of the inactive phosphorylated form of another pro-apoptotic BH3-only protein, Bad (i.e. as phospho-Bad). Knockout of Noxa or Puma suppressed apoptosis in response to TCRV infection, whereas silencing of Bad increased apoptosis, confirming that these factors are key regulators of apoptosis induction in response to TCRV infection. Further, we found that while the highly pathogenic JUNV does not induce caspase activation, it still activated upstream pro-apoptotic factors, consistent with current models suggesting that JUNV evades apoptosis by interfering with caspase activation through a nucleoprotein-mediated decoy function. This new mechanistic insight into the role that individual BH3-only proteins and their regulation play in controlling apoptotic fate in arenavirus-infected cells provides an important experimental framework for future studies aimed at dissecting differences in the apoptotic responses between arenaviruses, their connection to other cell signaling events and ultimately the relationship of these processes to pathogenesis.
Identifiants
pubmed: 33045019
doi: 10.1371/journal.ppat.1008948
pii: PPATHOGENS-D-20-01186
pmc: PMC7598930
doi:
Substances chimiques
Apoptosis Regulatory Proteins
0
BAD protein, human
0
BBC3 protein, human
0
PMAIP1 protein, human
0
Proto-Oncogene Proteins
0
Proto-Oncogene Proteins c-bcl-2
0
bcl-Associated Death Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008948Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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