title: Proprotein convertase subtilisin/kexin type 7 (PCSK7) is essential for the zebrafish development and bioavailability of transforming growth factor β1a (TGFβ1a).
abstract: Proprotein convertase subtilisin/kexin (PCSK) enzymes convert proproteins into bioactive end products. Although other PCSK enzymes are known to be essential for biological processes ranging from cholesterol metabolism to host defense, the in vivo importance of the evolutionarily ancient PCSK7 has remained enigmatic. Here, we quantified the expressions of all pcsk genes during the 1st week of fish development and in several tissues. pcsk7 expression was ubiquitous and evident already during the early development. To compare mammalian and zebrafish PCSK7, we prepared homology models, which demonstrated remarkable structural conservation. When the PCSK7 function in developing larvae was inhibited, we found that PCSK7-deficient fish have defects in various organs, including the brain, eye, and otic vesicle, and these result in mortality within 7 days postfertilization. A genome-wide analysis of PCSK7-dependent gene expression showed that, in addition to developmental processes, several immune system-related pathways are also regulated by PCSK7. Specifically, the PCSK7 contributed to the mRNA expression and proteolytic cleavage of the cytokine TGFβ1a. Consequently, tgfβ1a morphant fish displayed phenotypical similarities with pcsk7 morphants, underscoring the importance of this cytokine in the zebrafish development. Targeting PCSK activity has emerged as a strategy for treating human diseases. Our results suggest that inhibiting PCSK7 might interfere with normal vertebrate development.
authors.affiliation: From Immunoregulation.
authors.forename: Hannu
authors.initials: H
authors.lastname: Turpeinen
authors.forename: Anna
authors.initials: A
authors.lastname: Oksanen
authors.forename: Virpi
authors.initials: V
authors.lastname: Kivinen
authors.forename: Sampo
authors.initials: S
authors.lastname: Kukkurainen
authors.forename: Annemari
authors.initials: A
authors.lastname: Uusimäki
authors.forename: Mika
authors.initials: M
authors.lastname: Rämet
authors.forename: Mataleena
authors.initials: M
authors.lastname: Parikka
authors.forename: Vesa P
authors.initials: VP
authors.lastname: Hytönen
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D020134:Catalytic Domain; D017124:Conserved Sequence; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D008969:Molecular Sequence Data; D009928:Organ Specificity; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017385:Sequence Homology; D013381:Subtilisins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D029961:Zebrafish Proteins; C586747:tgfb1a protein, zebrafish; C099101:PCSK7 protein, human; C586746:PCSK7 protein, zebrafish; D013381:Subtilisins
keywords: Development; Gene Expression; Homology Modeling; Otolith; PC7; PCSK7; Proprotein Convertase; Protease; Transforming Growth Factor β (TGFβ); Zebrafish