The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication.
Basic-Leucine Zipper Transcription Factors
/ genetics
Cycloheximide
/ pharmacology
Endosomal Sorting Complexes Required for Transport
/ antagonists & inhibitors
Gene Expression Regulation
Gene Products, tax
/ genetics
HEK293 Cells
HeLa Cells
Human T-lymphotropic virus 1
/ drug effects
Human T-lymphotropic virus 2
/ drug effects
Humans
Lysosomes
/ drug effects
Macrolides
/ pharmacology
Phosphoproteins
/ genetics
Retroviridae Proteins
/ genetics
Signal Transduction
Virus Replication
/ drug effects
ESCRT
HRS
HTLV-1
HTLV-2
lysosomes
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
12 12 2019
12 12 2019
Historique:
received:
06
08
2019
accepted:
01
10
2019
pubmed:
11
10
2019
medline:
12
6
2020
entrez:
11
10
2019
Statut:
epublish
Résumé
The divergent clinical outcomes of human T cell leukemia virus type 1 (HTLV-1) and HTLV-2 infections have been attributed to functional differences in their antisense proteins. In contrast to HTLV-1 bZIP factor (HBZ), the role of the antisense protein of HTLV-2 (APH-2) in HTLV-2 infection is poorly understood. In previous studies, we identified the endosomal sorting complex required for transport 0 (ESCRT-0) subunit HRS as a novel interaction partner of APH-2 but not HBZ. HRS is a master regulator of endosomal protein sorting for lysosomal degradation and is hijacked by many viruses to promote replication. However, no studies to date have shown a link between HTLVs and HRS. In this study, we sought to characterize the interaction between HRS and APH-2 and to investigate the impact of HRS on the life cycle of HTLV-2. We confirmed a direct specific interaction between APH-2 and HRS and showed that the CC2 domain of HRS and the N-terminal domain of APH-2 mediate their interaction. We demonstrated that HRS recruits APH-2 to early endosomes, possibly furnishing an entry route into the endosomal/lysosomal pathway. We demonstrated that inhibition of this pathway using either bafilomycin or HRS overexpression substantially extends the half-life of APH-2 and stabilizes Tax2B expression levels. We found that HRS enhances Tax2B-mediated long terminal repeat (LTR) activation, while depletion of HRS enhances HTLV-2 production and release, indicating that HRS may have a negative impact on HTLV-2 replication. Overall, our study provides important new insights into the role of the ESCRT-0 HRS protein, and by extension the ESCRT machinery and the endosomal/lysosomal pathway, in HTLV-2 infection.
Identifiants
pubmed: 31597781
pii: JVI.01311-19
doi: 10.1128/JVI.01311-19
pmc: PMC6912118
pii:
doi:
Substances chimiques
Basic-Leucine Zipper Transcription Factors
0
Endosomal Sorting Complexes Required for Transport
0
Gene Products, tax
0
HBZ protein, human T-cell leukemia virus type I
0
Macrolides
0
Phosphoproteins
0
Retroviridae Proteins
0
hepatocyte growth factor-regulated tyrosine kinase substrate
0
tax2 protein, Human T-lymphotrophic virus 2
0
bafilomycin A
116764-51-3
Cycloheximide
98600C0908
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2019 American Society for Microbiology.
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