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

Abstract

eThe 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␤ [IL-1␤]), 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 ProArg 41 2 (where the down arrow indicates the cleavage location), and potentially by PCs at Arg 41 XXXXArg 46 2. 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 Arg 46 2. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIVinduced neuroinflammation, viral infection, and potentially the development of HAND.

Thrombotic characteristics of extracellular vesicles derived from prostate cancer cells

“…CHO cells were transfected to express the dual tagged PAR‐1 using the same protocol used to generate EGFRvIII. The plasmid construct of the human protease activated‐receptor one with fluorescent tags was provided as a generous gift from Dr Nabil Seidah (Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada) . TF silencing was carried out using lentiviral particles carrying a human TF‐ specific shRNA sequence and as described in …”

The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

“…Indeed, it was recently shown that in an effort to limit viral infections, host cells that are infected by a number of viruses provoke an interferon response to inhibit the enzymatic activity of furin-like enzymes. It was also demonstrated that HIV infection induces the expression of either the protease activated receptor 1 (PAR1) (Kim et al, 2015) or guanylate binding proteins 2 and 5 (GBP2,5) (Braun and Sauter, 2019) that restrict the trafficking of furin to the trans Golgi network (PAR1) or to early Golgi compartments (GBP2,5) where the proprotein convertase remains inactive. Altogether, these observations suggest that inhibitors of furin-like enzymes may contribute to inhibiting virus propagation.…”

A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin

“…Actually, it has been recently demonstrated that HCs infected by several kinds of viruses stimulate an interferon-based activity to block the enzymatic activity of furin-like enzymes (Lodermeyer et al, 2013). It was also revealed that virus infection triggers the upregulation of some receptors (Braun & Sauter, 2019;Kim et al, 2015) that inhibit the furin trafficking in post-Golgi compartments.…”