Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder.
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.
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
WooJin
W
Kim
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Erin
E
Zekas
Laboratory of Human Retrovirology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Robert
R
Lodge
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Delia
D
Susan-Resiga
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Edwidge
E
Marcinkiewicz
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Rachid
R
Essalmani
Inflammation Research Network, Snyder Institute for Chronic Diseases, and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Koichiro
K
Mihara
Inflammation Research Network, Snyder Institute for Chronic Diseases, and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Rithwik
R
Ramachandran
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Eugene
E
Asahchop
Departments of Pathology and Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Benjamin
B
Gelman
Laboratory of Human Retrovirology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Éric A
ÉA
Cohen
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Christopher
C
Power
Inflammation Research Network, Snyder Institute for Chronic Diseases, and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Morley D
MD
Hollenberg
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada seidahn@ircm.qc.ca.
Nabil G
NG
Seidah
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045683:Furin / Q000235:genetics; D005786:Gene Expression Regulation; D019302:HIV Envelope Protein gp160 / Q000378:metabolism; D015658:HIV Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D019965:Neurocognitive Disorders / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045702:Proprotein Convertase 5 / Q000032:analysis / Q000378:metabolism; D043484:Proprotein Convertases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D044463:Receptor, PAR-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013381:Subtilisins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
D019302:HIV Envelope Protein gp160; D012333:RNA, Messenger; D044463:Receptor, PAR-1; C080654:PCSK6 protein, human; C099101:PCSK7 protein, human; D045702:Proprotein Convertase 5; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D013381:Subtilisins; D013917:Thrombin; D045683:Furin