Furin

Function

The protein encoded by this gene is an enzyme that belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can efficiently cleave precursor proteins at their paired basic amino acid processing sites. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called hemojuvelin), a gene involved in a severe iron-overload disorder called juvenile hemochromatosis. Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.

The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP and PiTou.

Clinical significance

Furin is one of the proteases responsible for the proteolytic cleavage of HIV envelope polyprotein precursor gp160 to gp120 and gp41 prior to viral assembly. This protease is also thought to play a role in tumor progression. The use of alternate polyadenylation sites has been found for the FURIN gene.

Furin is enriched in the Golgi apparatus, where it functions to cleave other proteins into their mature/active forms. Furin cleaves proteins just downstream of a basic amino acid target sequence (canonically, Arg-X-(Arg/Lys) -Arg'). In addition to processing cellular precursor proteins, furin is also used by a number of pathogens. For example, the envelope proteins of viruses such as HIV, influenza, dengue fever, several filoviruses including ebola and marburg virus, and the spike protein of SARS-CoV-2, must be cleaved by furin or furin-like proteases to become fully functional. When SARS-CoV-2 virus is being synthesized in an infected cell, furin or furin-like proteases cleave the spike protein into two portions (S1 and S2), which remain associated.

Anthrax toxin, Pseudomonas exotoxin, and papillomaviruses must be processed by furin during their initial entry into host cells. Inhibitors of furin are under consideration as therapeutic agents for treating anthrax infection.

Furin is regulated by cholesterol and substrate presentation. When cholesterol is high, furin traffics to GM1 lipid rafts. When cholesterol is low, furin traffics to the disordered region. This is speculated to contribute to cholesterol and age dependent priming of SARS-CoV.

Expression of furin in T-cells is required for maintenance of peripheral immune tolerance.

Interactions

Furin has been shown to interact with PACS1.

References

References

1. (December 1990). "Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site". Proceedings of the National Academy of Sciences of the United States of America.
2. (December 1991). "Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15". DNA and Cell Biology.
3. "Entrez Gene: FURIN furin (paired basic amino acid cleaving enzyme)".
4. (September 1986). "Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein". The EMBO Journal.
5. (2008). "Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site". Blood Cells, Molecules & Diseases.
6. (April 2008). "Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin". BMC Biochemistry.
7. (January 2004). "Prediction of proprotein convertase cleavage sites". Protein Engineering, Design & Selection.
8. (February 2012). "Computational prediction of furin cleavage sites by a hybrid method and understanding mechanism underlying diseases". Scientific Reports.
9. (November 1992). "Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160". Nature.
10. (October 2002). "Furin at the cutting edge: from protein traffic to embryogenesis and disease". Nature Reviews. Molecular Cell Biology.
11. (April 2020). "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade". Antiviral Research.
12. (May 2020). "A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells". Molecular Cell.
13. (11 October 2021). "The origin of COVID-19: Evidence piles up, but the jury's still out".
14. (2022). "Mechanisms of SARS-CoV-2 entry into cells". [[Nature Reviews Molecular Cell Biology]].
15. (July 2007). "Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens". The Journal of Biological Chemistry.
16. (2023). "The role of high cholesterol in SARS-CoV-2 infectivity". Journal of Biological Chemistry.
17. (September 2008). "T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance". Nature.
18. (July 1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization". Cell.