HIV-1 Nef-Induced Secretion of the Proinflammatory Protease TACE into Extracellular Vesicles Is Mediated by Raf-1 and Can Be Suppressed by Clinical Protein Kinase Inhibitors.
ADAM17 Protein
/ metabolism
Extracellular Vesicles
/ metabolism
HEK293 Cells
HIV Infections
/ virology
HIV-1
/ physiology
HIV-2
/ physiology
Humans
Proto-Oncogene Proteins c-hck
/ metabolism
Proto-Oncogene Proteins c-raf
/ metabolism
Simian Immunodeficiency Virus
/ physiology
THP-1 Cells
Viral Regulatory and Accessory Proteins
/ metabolism
nef Gene Products, Human Immunodeficiency Virus
/ metabolism
ADAM17
HIV-1
Hck
Nef
Raf
TACE
extracellular vesicles
kinase inhibitor
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
12 04 2021
12 04 2021
Historique:
received:
03
02
2021
accepted:
10
02
2021
pubmed:
19
2
2021
medline:
14
5
2021
entrez:
18
2
2021
Statut:
epublish
Résumé
Chronic immune activation is an important driver of human immunodeficiency virus type 1 (HIV-1) pathogenesis and has been associated with the presence of tumor necrosis factor-α converting enzyme (TACE) in extracellular vesicles (EVs) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase hematopoietic cell kinase (Hck) by HIV-1 Nef can trigger the packaging of TACE into EVs via an unconventional protein secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and simian immunodeficiency virus (SIV) Nef alleles, we now show that the capacity to promote TACE secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger the secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of unconventional protein secretion and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation.
Identifiants
pubmed: 33597213
pii: JVI.00180-21
doi: 10.1128/JVI.00180-21
pmc: PMC8104104
pii:
doi:
Substances chimiques
NEF protein, SIV
0
Viral Regulatory and Accessory Proteins
0
nef Gene Products, Human Immunodeficiency Virus
0
nef protein, Human immunodeficiency virus 1
0
nef protein, Human immunodeficiency virus 2
0
HCK protein, human
EC 2.7.10.2
Proto-Oncogene Proteins c-hck
EC 2.7.10.2
Proto-Oncogene Proteins c-raf
EC 2.7.11.1
Raf1 protein, human
EC 2.7.11.1
ADAM17 Protein
EC 3.4.24.86
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 American Society for Microbiology.
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