1. The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication.
- Author
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Martini F, Arone C, Hasset A, Hall WW, and Sheehy N
- Subjects
- Basic-Leucine Zipper Transcription Factors genetics, Basic-Leucine Zipper Transcription Factors metabolism, Cycloheximide pharmacology, Endosomal Sorting Complexes Required for Transport antagonists & inhibitors, Endosomal Sorting Complexes Required for Transport metabolism, Gene Expression Regulation, Gene Products, tax metabolism, HEK293 Cells, HeLa Cells, Human T-lymphotropic virus 1 drug effects, Human T-lymphotropic virus 1 genetics, Human T-lymphotropic virus 1 metabolism, Human T-lymphotropic virus 1 pathogenicity, Human T-lymphotropic virus 2 drug effects, Human T-lymphotropic virus 2 metabolism, Human T-lymphotropic virus 2 pathogenicity, Humans, Lysosomes drug effects, Lysosomes metabolism, Lysosomes virology, Macrolides pharmacology, Phosphoproteins metabolism, Retroviridae Proteins metabolism, Signal Transduction, Virus Replication drug effects, Endosomal Sorting Complexes Required for Transport genetics, Gene Products, tax genetics, Human T-lymphotropic virus 2 genetics, Phosphoproteins genetics, Retroviridae Proteins genetics
- Abstract
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. IMPORTANCE While APH-2 is the only viral protein consistently expressed in infected carriers, its role in HTLV-2 infection is poorly understood. In this study, we characterized the interaction between the ESCRT-0 component HRS and APH-2 and explored the role of HRS in HTLV-2 replication. HRS is a master regulator of protein sorting for lysosomal degradation, a feature that is manipulated by several viruses to promote replication. Unexpectedly, we found that HRS targets APH-2 and possibly Tax2B for lysosomal degradation and has an overall negative impact on HTLV-2 replication and release. The negative impact of interactions between HTLV-2 regulatory proteins and HRS, and by extension the ESCRT machinery, may represent an important strategy used by HTLV-2 to limit virus production and to promote persistence, features that may contribute to the limited pathogenic potential of this infection., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
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