HIV-induced neuroinflammation

impact of PAR1 and PAR2 processing by Furin

Vatsal Sachan, Robert Lodge, Koichiro Mihara, Josée Hamelin, Christopher Power, Benjamin Gelman, Morley D. Hollenberg, Éric A. Cohen, Nabil G. Seidah

Research output: Contribution to journalArticle

Abstract

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 R41XXXXR46↓ 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 R31XXXXR36↓ 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 Asn47 in PAR1 for its Furin-dependent TGN localization. Our data revealed that Furin is the only convertase that efficiently cleaves PAR2 at Arg36↓. N-glycosylation of PAR2 at Asn30 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.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Furin
HIV
Proprotein Convertases
trans-Golgi Network
Protein Transport
HIV-1
PAR-2 Receptor
PAR-1 Receptor
Biological Phenomena
Basic Amino Acids
Protein Precursors
Neurotoxins
Coculture Techniques
Neuroblastoma
Glycosylation
Free Radicals
Tail
Cell Survival
Peptide Hydrolases
Central Nervous System

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Sachan, V., Lodge, R., Mihara, K., Hamelin, J., Power, C., Gelman, B., ... Seidah, N. G. (Accepted/In press). HIV-induced neuroinflammation: impact of PAR1 and PAR2 processing by Furin. Cell Death and Differentiation. https://doi.org/10.1038/s41418-018-0264-7

HIV-induced neuroinflammation : impact of PAR1 and PAR2 processing by Furin. / Sachan, Vatsal; Lodge, Robert; Mihara, Koichiro; Hamelin, Josée; Power, Christopher; Gelman, Benjamin; Hollenberg, Morley D.; Cohen, Éric A.; Seidah, Nabil G.

In: Cell Death and Differentiation, 01.01.2019.

Research output: Contribution to journalArticle

Sachan, V, Lodge, R, Mihara, K, Hamelin, J, Power, C, Gelman, B, Hollenberg, MD, Cohen, ÉA & Seidah, NG 2019, 'HIV-induced neuroinflammation: impact of PAR1 and PAR2 processing by Furin', Cell Death and Differentiation. https://doi.org/10.1038/s41418-018-0264-7
Sachan, Vatsal ; Lodge, Robert ; Mihara, Koichiro ; Hamelin, Josée ; Power, Christopher ; Gelman, Benjamin ; Hollenberg, Morley D. ; Cohen, Éric A. ; Seidah, Nabil G. / HIV-induced neuroinflammation : impact of PAR1 and PAR2 processing by Furin. In: Cell Death and Differentiation. 2019.
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abstract = "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 R41XXXXR46↓ 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 R31XXXXR36↓ 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 Asn47 in PAR1 for its Furin-dependent TGN localization. Our data revealed that Furin is the only convertase that efficiently cleaves PAR2 at Arg36↓. N-glycosylation of PAR2 at Asn30 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.",
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AU - Sachan, Vatsal

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AU - Hamelin, Josée

AU - Power, Christopher

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AU - Hollenberg, Morley D.

AU - Cohen, Éric A.

AU - Seidah, Nabil G.

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