Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder.

TitleNeuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder.
Publication TypeJournal Article
Year of Publication2015
AuthorsKim, WJ, Zekas, E, Lodge, R, Susan-Resiga, D, Marcinkiewicz, E, Essalmani, R, Mihara, K, Ramachandran, R, Asahchop, EL, Gelman, B, Cohen, ÉA, Power, C, Hollenberg, MD, Seidah, NG
JournalMol Cell Biol
Volume35
Issue21
Pagination3684-700
Date Published2015 Nov
ISSN1098-5549
KeywordsAmino Acid Sequence, Animals, Brain, Cell Line, External, Furin, Gene Expression Regulation, HIV Envelope Protein gp160, HIV Infections, HIV-1, Host-Pathogen Interactions, Humans, Inflammation, Mice, Molecular Sequence Data, neurocognitive disorders, Proprotein Convertase 5, Proprotein Convertases, Protein Interaction Maps, Receptor, PAR-1, RNA, Messenger, Serine Endopeptidases, Subtilisins, Thrombin
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-1β [IL-1β]), 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.

DOI10.1128/MCB.00764-15
Alternate JournalMol. Cell. Biol.
PubMed ID26283733
PubMed Central IDPMC4589605
Grant ListU24 MH100930 / MH / NIMH NIH HHS / United States
U24MH100930 / MH / NIMH NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada