Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)

Turpeinen, Hannu; Oksanen, Anna; Kivinen, Virpi; Kukkurainen, Sampo; Uusimäki, Annemari; Rämet, Mika; Parikka, Mataleena; Hytönen, Vesa P.; Nykter, Matti; Pesu, Marko

doi:10.1074/jbc.m113.453183

Cited by 15 publications

(18 citation statements)

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“…2A), which is in line with the previously reported ubiquitous expression pattern of FURIN orthologues in vertebrates (9,32). In mammals, the first seven PCSK enzymes have been demonstrated to exhibit a significant functional redundancy and shared substrate molecules, which interferes with the interpretation of a PCSK specific phenotype (39).…”

Section: Resultssupporting

confidence: 67%

“…Since furinA regulated the granulopoiesis, we addressed its role in innate immunity by inhibiting the expressions of furinA and furinB in the embryonic M. marinum infection model (27,32,33). Infecting either control (random control MO injected [RC]) or the double furin gene knockdown embryos with M. marinum (131 Ϯ 125 CFU) resulted in substantial lethality by 7 days postinfection (dpi; 93 and 100%, respectively, Fig.…”

Section: Resultsmentioning

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). Two orthologous genes of mammalian FURIN, furinA and furinB (30), were found to be ubiquitously expressed, and biochemical analyses The M. marinum burden of furinA td204e/ϩ mutants (n ϭ 17 to 20) and WT controls (n ϭ 13 to 18) was quantified with DNA qRT-PCR at 4 and 9 wpi.…”

Section: Discussionmentioning

confidence: 99%

“…showed that FurinA, but not FurinB, is able to proteolytically process pro-Tgfb1a, suggesting that FurinA is the corresponding biological equivalent for human FURIN (32). Germ line Furin KO mice die on day 11 of embryogenesis due to severe developmental defects in ventral closure, as well as in heart tube fusion and looping (20).…”

Section: Discussionmentioning

confidence: 99%

“…Oligonucleotide sequences for furinA and furinB gene silencing morpholinos (MOs) and the injection protocol have been previously described (32). The injection volume was set to 2 nl, and 0.25 pmol of both furinA and furinB MOs or 0.5 pmol of RC MO was used.…”

Section: Mo and M Marinum Coinjectionsmentioning

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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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: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%