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  • Review Article
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Furin at the cutting edge: From protein traffic to embryogenesis and disease

Key Points

  • Furin is a ubiquitous proprotein convertase that cleaves substrates at the consensus sequence –Arg–X–Lys/Arg–Arg–. In exceptional cases, –Lys/Arg–X–X–X–Lys/Arg–Arg– is cleaved. Furin has greater than 50% activity at pH 5–8 and, like other subtilisin superfamily serine endoproteases, is strictly calcium dependent.

  • The prodomain of furin is an intramolecular chaperone that guides enzyme folding and activation. Furin exploits its own cleavage-site rules to cut the prodomain twice during activation — first, at neutral pH in the endoplasmic reticulum at a consensus furin site, and second, after the pH-sensitive furin site –Arg70–Gly–Val–Thr–Lys–Arg75– in the mildly acidic trans-Golgi network (TGN)/endosomal system.

  • Furin localizes to the TGN and follows a highly regulated trafficking itinerary through TGN/endosomal compartments and the cell surface, an itinerary that enables it to activate diverse proproteins in vivo. Furin's itinerary is controlled by the interaction between trafficking motifs in its cytoplasmic domain and sorting proteins. The casein kinase 2-phosphorylated acidic cluster binds to phosphofurin acidic cluster sorting protein-1, which links furin to adaptor protein (AP)-1 and directs retrieval to the TGN. The protein phosphatase 2A-dephosphorylated acidic cluster controls endosomal sorting. Basolateral targeting of furin is controlled by AP-4, and furin endocytosis is directed by AP-2. Cell-surface furin is tethered by the actin-binding protein filamin.

  • Furin has fundamental roles in embryogenesis, homeostasis and disease. Processing of pro-β-nerve growth factor (NGF) controls whether the neurotrophin activates cell-survival or cell-death pathways. Furin's role in the secretase-mediated processing of amyloid precursor protein (APP) helps determine whether APP peptides enhance NGF signalling or cause neurodegeneration. Furin also controls the signalling range of tumour necrosis factor-α and transforming growth factor (TGF)-β family members.

  • Although TGF-β activation by furin is essential for embryogenesis, this pathway exacerbates rheumatoid arthritis in adults. Furin is upregulated in several cancers, and increased furin levels correlate with increased levels of several of its processed substrates, including membrane-type-1 matrix metalloproteinase, insulin-like growth factor-1 and its receptor IGF-1R, and with greater tumour aggressiveness.

  • Furin activates numerous bacterial toxins and pathogenic viruses. For example, cell-surface furin activates anthrax toxin, and early endosomal furin activates several A/B type toxins, including Pseudomonas exotoxin A, shiga toxin and diphtheria toxins. Many pathogenic viruses, including avian influenza virus, HIV-1 and measles virus, express envelope glycoproteins that require processing at consensus furin sites to form mature, fusogenic molecules. Additionally, the virulence of many deadly viruses, including Ebola virus, is directly correlated with the ability of the virus to incorporate a consensus furin cleavage site within its envelope proteins. Inhibition of furin blocks both pathogen activation and tumour metastasis.

Abstract

Furin catalyses a simple biochemical reaction — the proteolytic maturation of proprotein substrates in the secretory pathway. But the simplicity of this reaction belies furin's broad and important roles in homeostasis, as well as in diseases ranging from Alzheimer's disease and cancer to anthrax and Ebola fever. This review summarizes various features of furin — its structural and enzymatic properties, intracellular localization, trafficking, substrates, and roles in vivo.

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Figure 1: Schematic diagram of the proprotein convertase (PC) family.
Figure 2: Furin-processing compartments of the trans-Golgi network (TGN)/endosomal system.
Figure 3: The furin autoactivation pathway.
Figure 4: Model of furin trafficking.
Figure 5: The sorting motifs of the furin cytoplasmic domain.
Figure 6: Furin in development, homeostasis and disease.
Figure 7: Furin activation of the anthrax toxin.

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Acknowledgements

My apologies to colleagues whose work I did not cite because of space limitations. Special thanks go to A. Zhou, D. Steiner, members of my lab and collaborators for insightful discussions and review of the manuscript, and to R. Dresbeck for editing. G.T. is supported by grants from the National Institutes of Health.

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DATABASES

InterPro

P domain

LocusLink

AP-1

AP-2

AP-4

BRI

CK2

filamin

IGF1

MAPK

PP2A

protein kinase C

TGF-β

TNF

OMIM

Alzheimer's disease

familial British dementia

familial Danish dementia

rheumatoid arthritis

Swiss-Prot

ADAM10

ADAM17

ADAMTS-4

APP

APRIL

ARF1

ATR

BAFF

BMP-4

CI-MPR

CPD

EDAR

EF

Furin

gelsolin

GGA3

HA

IGF1R

KIF13A

Lefty-2

LF

MMP2

MT1-MMP

β-NGF

Nodal

PA

PACE4

PACS-1

PC5/6A

PC5/6B

PC7

RAB6

β-secretase

SMAD2

SNX-15

Sortilin

TGF-β1

TNF-α

FURTHER INFORMATION

Gary Thomas' lab

Glossary

ENDOPROTEASE

An enzyme that hydrolyses peptide and protein substrates at specific internal peptide bonds. By contrast, exoproteases remove either the carboxy-terminal (carboxypeptidase) or amino-terminal (aminopeptidase) residues.

PROPROTEIN

A precursor protein that is proteolytically cleaved, typically at sites formed by doublets or clusters of basic amino acids, to produce the mature and active protein or, in the case of prohormones, the mature peptide hormones.

PATHOGENICITY

A measure of the ability of a pathogen to invade a host and cause disease. The degree of the pathogenicity is measured as its virulence.

TYPE-I TRANSMEMBRANE PROTEIN

Proteins that contain a single membrane-spanning domain, with the carboxyl terminus oriented towards the cytoplasm and the amino terminus oriented towards the lumen of membrane compartments or extracellularly.

PROPROTEIN CONVERTASE

Members of the family of calcium-dependent, subtilisin-like serine endoproteases that are structurally related to Kex2 and furin and that cleave proprotein substrates at the carboxy-terminal side of doublets or clusters of basic amino acids.

α-MATING PHEROMONE

A peptide pheromone that is secreted by yeast alpha-cells to stimulate mating with yeast a-cells. The α-mating pheromone is synthesized as a proprotein substrate that is cleaved by Kex2. Yeast alpha-cells lacking Kex2 are sterile.

SUBTILISIN SUPERFAMILY

The serine proteases are composed of the subtilisin and chymotrypsin (including trypsin, thrombin and elastase) superfamilies. Surprisingly, the two superfamilies are evolutionarily distinct, yet the atoms that form the catalytic centre are in nearly identical positions — a remarkable example of convergent evolution.

CATALYTIC TRIAD

In serine endoproteases, the catalytic triad comprises the three spatially-optimized active-site residues — serine, histidine and aspartate — that conspire to bring about peptide-bond hydrolysis.

BACTERIAL THERMITASE

A thermostable bacterial subtilisin with a solved crystal structure.

P1 AND P4

A broadly used nomenclature that identifies the amino-acid residues that flank the cleavage site (scissile bond) in protein and peptide substrates. The amino acid that is amino-terminal to the scissile bond is designated P1. P2 is the amino acid that is amino-terminal to P1. So, P4 is the amino acid that is four residues to the amino-terminal side of the scissile bond. The amino acids that are carboxy-terminal to the scissile bond are labelled P1′, P2′, and so on.

α1-ANTITRYPSIN

The circulating protein inhibitor of neutrophil elastase. It inhibits serine proteases by acting as a slow tight-binding inhibitor or suicide substrate. Inhibitors that use this type of mechanism are called serpins. The reactive site, which lures the protease, can be engineered to target specific proteases.

Ki

The inhibitor constant that describes the dissociation of an enzyme (E)–inhibitor (I) complex, Ki = [E][I]/[EI].

JUXTACRINE VERSUS PARACRINE

Juxtacrine is communication between adjacent cells, whereas paracrine is communication between cells that are further apart.

CIS VERSUS TRANS CLEAVAGE

cis cleavage refers to the autoproteolytic intramolecular cleavage of an endoprotease propeptide by the catalytic triad that is part of the same molecule. trans cleavage refers to the processing of other molecules.

ANTEROGRADE AND RETROGRADE

Anterograde refers to trafficking from the endoplasmic reticulum (ER) towards the plasma membrane, whereas retrograde refers to trafficking from the plasma membrane towards the ER.

REGULATED VERSUS CONSTITUTIVE PATHWAYS

The regulated pathway in endocrine and neuroendocrine cells constitutes the anterograde pathway, leading from the trans-Golgi network (TGN) to the peptide-hormone-containing, mature secretory granules that can be stimulated to exocytose following an influx of extracellular calcium. Secretion by the constitutive pathway is not stimulated by calcium.

NEUROTROPHINS

A class of molecules that control various aspects of neuronal survival and plasticity, and that include nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5. The neurotrophins are synthesized as proproteins that require cleavage at consensus furin sites.

AMYLOID DEMENTIA

Neurological abnormality caused by deposits of proteinaceous matter.

ENAMEL KNOT

Signalling centre in the dental epithelium that controls tooth morphogenesis.

MORPHOGENS

Secreted signalling molecules that govern developmental patterns and axis formation by producing a concentration gradient emanating from the cells in which they are synthesized.

GLIOBLASTOMAS

Aggressive malignant brain tumours that are derived from astrocytes and that account for 30% of all primary brain tumours.

NEOVASCULARIZATION

De novo stimulation of new blood supplies to a growing tumour.

ALVEOLIZATION

Encompasses the latter stages of lung development, which begin with bronchial and respiratory-tree development, and culminate in the formation of terminal saccules and alveoli to facilitate efficient gas exchange.

SEC61 CHANNEL

The main protein that forms the pore in the endoplasmic reticulum (ER) membrane that facilitates the translocation of nascently synthesized proteins into the secretory pathway. The SEC61 channel might also be a conduit for the reverse translocation (dislocation) of proteins from the ER into the cytoplasm.

KDEL RECEPTOR

Golgi-localized membrane protein that binds to carboxy-terminal KDEL (–Lys–Asp–Glu–Leu–) motifs, which are present on many resident endoplasmic reticulum (ER) proteins that escape to the Golgi, and that retrieves them to the ER.

COPI

(Coatomer protein complex I). A specific type of coat on vesicles that traffic principally between Golgi cisternae and from the Golgi to the endoplasmic reticulum. Also reported on early endosomes.

VIRULENCE

The extent or degree to which a pathogen can cause disease.

INFECTIVITY

The ability of a pathogen to invade a host and replicate, irrespective of its ability to cause disease.

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Thomas, G. Furin at the cutting edge: From protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3, 753–766 (2002). https://doi.org/10.1038/nrm934

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