HIV-induced neuroinflammation: impact of PAR1 and PAR2 processing by Furin

HIV-associated neurocognitive disorders (HAND) is a syndrome defined by neurocognitive deficits that are driven by viral neurotoxins, cytokines, free radicals, and proteases expressed in the brain. This neurological disease has also been linked to activation of Protease-Activated Receptors 1 and 2 (...

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Bibliographic Details
Published in:Cell death and differentiation 2019-10, Vol.26 (10), p.1942-1954
Main Authors: Sachan, Vatsal, Lodge, Robert, Mihara, Koichiro, Hamelin, Josée, Power, Christopher, Gelman, Benjamin B, Hollenberg, Morley D, Cohen, Éric A, Seidah, Nabil G
Format: Article
Language:English
Subjects:
Brain research
Cell viability
Central nervous system
Cognition
Cytokines
Cytotoxicity
Free radicals
Furin
Glycosylation
Golgi apparatus
HIV
Human immunodeficiency virus
Inflammation
Laboratories
Ligands
Localization
Macrophages
Medicine
Mortality
Nervous system
Neuroblastoma
Neurological diseases
Neurotoxins
Proprotein convertases
Protein transport
Proteins
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Summary:HIV-associated neurocognitive disorders (HAND) is a syndrome defined by neurocognitive deficits that are driven by viral neurotoxins, cytokines, free radicals, and proteases expressed in the brain. This neurological disease has also been linked to activation of Protease-Activated Receptors 1 and 2 (PAR1,2). These receptors are highly expressed in the central nervous system and are upregulated in HAND. Secretory basic-amino-acid-specific Proprotein Convertases (PCs), which cleave precursor proteins at basic residues, are also induced in HAND. They are vital for many biological processes including HIV-1 entry into cells. The cytoprotective role of Furin, PC5, and PACE4 has been linked to the presence of a potential PC-cleavage site R XXXXR ↓ in PAR1. Furthermore, Furin binds PAR1 and both are trapped in the trans-Golgi-network (TGN) as inactive proteins, likely due to the intermediary trafficking role of phospho-Furin acidic cluster sorting protein 1 (PACS1). Nothing is known about PAR2 and its possible recognition by PCs at its putative R XXXXR ↓ processing site. The present study implicates PACS1 in the retrograde trafficking of PAR1 to the TGN and demonstrates that the cytosolic extreme C-terminal tail of PAR1 contains an acidic phosphorylatable PACS1-sensitive domain. We further show the requirement of Asn in PAR1 for its Furin-dependent TGN localization. Our data revealed that Furin is the only convertase that efficiently cleaves PAR2 at Arg ↓. N-glycosylation of PAR2 at Asn reduces the efficacy, but enhances selectivity of the Furin cleavage. Finally, in co-cultures comprised of human neuroblastoma SK-N-SH cells (stably expressing PAR1/2 and/or Furin) and HIV-1-infected primary macrophages, we demonstrate that the expression of Furin enhances neuronal cell viability in the context of PAR1- or PAR2-induced neuronal cytotoxicity. The present study provides insights into early stages of HIV-1 induced neuronal injury and the protective role of Furin in neurons co-expressing PAR1 and/or PAR2, as observed in HAND.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-018-0264-7