Neuroinflammation-induced interactions between protease-activated receptor 1 and proprotein convertases in HIV-associated neurocognitive disorder

Woo Jin Kim, Erin Zekas, Robert Lodge, Delia Susan-Resiga, Edwidge Marcinkiewicz, Rachid Essalmani, Koichiro Mihara, Rithwik Ramachandran, Eugene Asahchop, Benjamin Gelman, Éric A. Cohen, Christopher Power, Morley D. Hollenberg, Nabil G. Seidah

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1ß [IL-1ß]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓(where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND.

Original languageEnglish (US)
Pages (from-to)3684-3700
Number of pages17
JournalMolecular and Cellular Biology
Volume35
Issue number21
DOIs
StatePublished - 2015

Fingerprint

Proprotein Convertases
PAR-1 Receptor
Furin
HIV
HIV Envelope Protein gp160
Thrombin
Proprotein Convertase 5
Inflammation
Human Immunodeficiency Virus Proteins
trans-Golgi Network
Messenger RNA
Virus Diseases
Neurocognitive Disorders
Interleukin-1
Ligation
Up-Regulation
Cell Membrane
Calcium
Gene Expression
Membranes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Neuroinflammation-induced interactions between protease-activated receptor 1 and proprotein convertases in HIV-associated neurocognitive disorder. / Kim, Woo Jin; Zekas, Erin; Lodge, Robert; Susan-Resiga, Delia; Marcinkiewicz, Edwidge; Essalmani, Rachid; Mihara, Koichiro; Ramachandran, Rithwik; Asahchop, Eugene; Gelman, Benjamin; Cohen, Éric A.; Power, Christopher; Hollenberg, Morley D.; Seidah, Nabil G.

In: Molecular and Cellular Biology, Vol. 35, No. 21, 2015, p. 3684-3700.

Research output: Contribution to journalArticle

Kim, WJ, Zekas, E, Lodge, R, Susan-Resiga, D, Marcinkiewicz, E, Essalmani, R, Mihara, K, Ramachandran, R, Asahchop, E, Gelman, B, Cohen, ÉA, Power, C, Hollenberg, MD & Seidah, NG 2015, 'Neuroinflammation-induced interactions between protease-activated receptor 1 and proprotein convertases in HIV-associated neurocognitive disorder', Molecular and Cellular Biology, vol. 35, no. 21, pp. 3684-3700. https://doi.org/10.1128/MCB.00764-15
Kim, Woo Jin ; Zekas, Erin ; Lodge, Robert ; Susan-Resiga, Delia ; Marcinkiewicz, Edwidge ; Essalmani, Rachid ; Mihara, Koichiro ; Ramachandran, Rithwik ; Asahchop, Eugene ; Gelman, Benjamin ; Cohen, Éric A. ; Power, Christopher ; Hollenberg, Morley D. ; Seidah, Nabil G. / Neuroinflammation-induced interactions between protease-activated receptor 1 and proprotein convertases in HIV-associated neurocognitive disorder. In: Molecular and Cellular Biology. 2015 ; Vol. 35, No. 21. pp. 3684-3700.
@article{f438adf0964543b3aca672441c79c2f1,
title = "Neuroinflammation-induced interactions between protease-activated receptor 1 and proprotein convertases in HIV-associated neurocognitive disorder",
abstract = "The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1{\ss} [IL-1{\ss}]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓(where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND.",
author = "Kim, {Woo Jin} and Erin Zekas and Robert Lodge and Delia Susan-Resiga and Edwidge Marcinkiewicz and Rachid Essalmani and Koichiro Mihara and Rithwik Ramachandran and Eugene Asahchop and Benjamin Gelman and Cohen, {{\'E}ric A.} and Christopher Power and Hollenberg, {Morley D.} and Seidah, {Nabil G.}",
year = "2015",
doi = "10.1128/MCB.00764-15",
language = "English (US)",
volume = "35",
pages = "3684--3700",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "21",

}

TY - JOUR

T1 - Neuroinflammation-induced interactions between protease-activated receptor 1 and proprotein convertases in HIV-associated neurocognitive disorder

AU - Kim, Woo Jin

AU - Zekas, Erin

AU - Lodge, Robert

AU - Susan-Resiga, Delia

AU - Marcinkiewicz, Edwidge

AU - Essalmani, Rachid

AU - Mihara, Koichiro

AU - Ramachandran, Rithwik

AU - Asahchop, Eugene

AU - Gelman, Benjamin

AU - Cohen, Éric A.

AU - Power, Christopher

AU - Hollenberg, Morley D.

AU - Seidah, Nabil G.

PY - 2015

Y1 - 2015

N2 - The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1ß [IL-1ß]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓(where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND.

AB - The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1ß [IL-1ß]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg41↓(where the down arrow indicates the cleavage location), and potentially by PCs at Arg41XXXXArg46↓. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg46↓. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIV-induced neuroinflammation, viral infection, and potentially the development of HAND.

UR - http://www.scopus.com/inward/record.url?scp=84944629624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84944629624&partnerID=8YFLogxK

U2 - 10.1128/MCB.00764-15

DO - 10.1128/MCB.00764-15

M3 - Article

VL - 35

SP - 3684

EP - 3700

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 21

ER -