Proprotein Convertases in Health and Disease

Artenstein, Andrew W.; Opal, Steven M.

doi:10.1056/nejmra1106700

Cited by 166 publications

(180 citation statements)

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“…Through catalyzing the endoproteolytic cleavage of target molecules, PCSK enzymes regulate the maturation of host defense factors, as well as the activity of invading pathogens (9,10). In vitro analyses have demonstrated that PCSK enzymes have significantly overlapping biochemical functions in substrate processing, and therefore genetic inactivation of PCSKs is instrumental for decoding their specific biological roles (9,10,47).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro analyses have demonstrated that PCSK enzymes have significantly overlapping biochemical functions in substrate processing, and therefore genetic inactivation of PCSKs is instrumental for decoding their specific biological roles (9,10,47). We have previously characterized the expression of seven pcsk genes in developing embryos and multiple adult zebrafish tissues (32).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, furinA downregulation in furinA td204e/ϩ mutant zebrafish upregulated pcsk1 and pcsk2 expression, which implies an attempt to compensate for the reduced FurinA activity. In mammals, PCSK1 and PCSK2 have restricted gene expression patterns, function chiefly in neuroendocrine tissues, and are not able to compensate for FURIN during development (9,10). However, the lack of PCSK1 was recently found to associate with a proinflammatory phenotype and increased lethality in LPS-induced septic shock in mice (48).…”

Section: Discussionmentioning

confidence: 99%

“…Typically, PCSKs convert precursor proteins (proproteins) into their biologically active forms by cleaving them at specific target motifs made up of the basic amino acids lysine and arginine (9,10). FURIN was the first identified mammalian PCSK and is present in vertebrates and many invertebrates (11,12).…”

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The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

et al. 2015

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Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinA td204e/؉ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinuminfected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinA td204e/؉ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinA td204e/؉ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection.T uberculosis (TB) is an epidemic infectious disease caused by the mycobacterial species Mycobacterium tuberculosis (1, 2). Circa 13% of the individuals with active TB were simultaneous carriers of the human immunodeficiency virus (HIV), and almost one-third of TB-associated deaths occurred among HIV ϩ patients, demonstrating the critical role of cluster of differentiation 4 (CD4 ϩ ) T lymphocyte-mediated immunity in the control of M. tuberculosis infection (3, 4). More specifically, the adaptive immunity against TB is primarily mediated by T helper (Th) type 1 cells, as is suggested by the gene expression profile upon infection (5), as well as the infection-induced mortality of gamma interferon-deficient (6, 7) and interleukin-12 (IL-12)-deficient (8) mice.The proprotein convertase subtilisin/kexin (PCSK) enzymes are a family of serine endoproteases with nine members in humans: PCSK1 and -2, FURIN, PCSK4 to -7, membrane-bound transcription factor peptidase site 1 (MBTPS1), and PCSK9 (9). Typically, PCSKs convert precursor proteins (proproteins) into their biologically active forms by cleaving them at specific target motifs made up of the basic amino acids lysine and arginine (9, 10). FURIN was the first identified mammalian PCSK and is present in vertebrates and many invertebrates (11,12). A series of in vitro experiments have suggested a central role for FURIN in host defense because it proteolytically activates several immunoregulatory proproteins, such as membrane-inserted matrix metallo...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum

et al. 2015

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“…al, 2014). PCSK9 was found through genetic studies documenting familial hypercholesterolemia and molecular studies that characterized it as a member of the proprotein convertase family of serine proteases that play a role in a range of metabolic, infectious, and neurodegenerative diseases (Artenstein and Opal, 2011). In humans, PCSK9 is primarily expressed in the liver, intestine, kidney, and brain, though recent studies have detected its expression in other tissues as well (Artenstein and Opal, 2011).…”

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confidence: 99%