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

15 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kim, W. J., Zekas, E., Lodge, R., Susan-Resiga, D., Marcinkiewicz, E., Essalmani, R., Mihara, K., Ramachandran, R., Asahchop, E., Gelman, B., Cohen, É. A., Power, C., Hollenberg, M. D., & Seidah, N. G. (2015). Neuroinflammation-induced interactions between protease-activated receptor 1 and proprotein convertases in HIV-associated neurocognitive disorder. Molecular and cellular biology, 35(21), 3684-3700. https://doi.org/10.1128/MCB.00764-15