NCBI Summary:
This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]
General function
Enzyme
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Follicle atresia
Comment
PCSK6 regulated by LH inhibits the apoptosis of human granulosa cells via activin A and TGF-2. Wang Y 2014 et al.
Mammalian proprotein convertases (PCs) play an important role in folliculogenesis, as they proteolytically activate a variety of substrates such as the transforming growth factor-beta (TGF-) superfamily. Proprotein convertase subtilism/kexin (PCSK) 6 is a member of the PC family and is ubiquitously expressed and implicated in many physiological and pathological processes. However, in human granulosa cells, the expression of the PC family members, their hormonal regulation and the function of PCs are not clear. Here, we find that PCSK6 is the most highly expressed PC family member in granulosa cells. Luteinizing hormone (LH) increased PCSK6 mRNA level and PCSK6 played an anti-apoptosis function in KGN. Knockdown of PCSK6 not only increased the secretion of activin A and TGF-2 but also decreased the secretion of follistatin, estrogen and the mRNA levels of follicle-stimulating hormone receptor (FSHR) and P450arom. We also found that in the KGN human granulosa cell line, TGF-2 and activin A could promote the apoptosis of KGN and LH could regulate the follistatin level. These data indicate that PCSK6, which is regulated by LH, is highly expressed in human primary granulosa cells of pre-ovulatory follicles and plays important roles in regulating a series of downstream molecules and KGN apoptosis.
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Expression regulated by
FSH, LH, Growth Factors/ cytokines
Comment
The Localization and Regulation of Proprotein Convertase Subtilisin/Kexin (PCSK) 6 in Human Ovary. Akiyama I et al. PROBLEM: The aim of this study is to evaluate the expression and regulation of proprotein convertase subtilisin/kexin (PCSK) 6, which is known to be an important factor in the production of bone morphogenetic protein (BMP) cytokines in human ovary. METHOD OF STUDY: The localization of PCSK 6 protein in normal human ovaries was examined by immunohistochemistry. Human granulosa cells (GC), obtained from 34 patients undergoing ovarian stimulation for in vitro fertilization, were cultured with BMP-2, BMP-6, BMP-7, BMP-15, growth differentiation factor (GDF)-9, and activin-A with or without FSH. PCSK 6 mRNA expression level was evaluated by quantitative real-time reverse transcription and polymerase chain reaction (RT-PCR). RESULTS: An immunohistochemistry study revealed that GC expressed PCSK 6 throughout follicular development, beginning in the primary follicle stage, while oocytes expressed PCSK 6 from the primordial follicle stage onwards. An in vitro study demonstrated that BMP-2, BMP-6, BMP-7, and BMP-15, not activin-A and GDF-9, decreased PCSK 6 gene expression in human GC. FSH induced PCSK 6 mRNA in the presence of activin-A or GDF-9. GDF-3, which is an inhibitor of BMP cytokines, also induced PCSK 6 mRNA expression. CONCLUSIONS: PCSK 6, which is a critical factor to produce BMP cytokines, was suppressed with BMP stimulation in human GC, suggesting the presence of a negative feedback system in the follicular development process.
Ovarian localization
Oocyte, Granulosa
Comment
Regulation of Pcsk6 Expression During the Preantral to Antral Follicle Transition in Mice: Opposing Roles of FSH and Oocytes. Diaz FJ et al. Several secreted products of the TGFbeta superfamily have important roles during follicular development and are produced by both oocytes and somatic cells (granulosa and theca) in the follicle. The proprotein convertases are a family of seven known proteins that process TGFbeta ligands and other secreted products to their mature active form. The present study examined the regulation of steady-state levels of Pcsk6 mRNA, which encodes a convertase protein known to process members of the TGFbeta superfamily, during mouse follicular development. Pcsk6 mRNA and protein were expressed in preantral but not cumulus or mural granulosa cells. Pcsk6 mRNA levels in preantral granulosa cells were not regulated by growing oocytes of preantral follicles, but were elevated by FSH. Furthermore, Pcsk6 mRNA in preantral granulosa cells was potently suppressed by factor(s) secreted by fully grown oocytes from antral follicles, in part through SMAD2/3-mediated pathways. Oocytes acquired the ability to suppress the steady-state levels Pcsk6 mRNA in granulosa cells during preantral to antral follicle transition. Suppression of Pcsk6 mRNA by oocytes could reflect a change in the mechanism(s) regulating the activity of members of the TGFbeta superfamily.
Follicle stages
Primary, Secondary
Comment
Phenotypes
POF (premature ovarian failure)
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Pcsk6 mutant mice exhibit progressive loss of ovarian function, altered gene expression, and formation of ovarian pathology. Mujoomdar ML et al. Bioactivation of precursor proteins by members of the proprotein convertase (PC) family is essential for normal reproduction. The Pcsk6 gene is a member of the PC family that is expressed in numerous ovarian cell types including granulosa cells and oocytes. We hypothesized that loss of PCSK6 would produce adverse effects in the mouse ovary. Mice incapable of expressing PCSK6 (Pcsk6tm1Rob) were obtained and reproductive parameters (serum hormones, whelping interval, estrus cyclicity, fertility) were compared to Pcsk6+/+ mice. While Pcsk6tm1Rob female mice are fertile, they manifest reduced reproductive capacity at an accelerated rate relative to Pcsk6+/+ mice. Reproductive senescence is typically reached by 9 months of age and is correlated with loss of estrus cyclicity, elevated serum FSH levels, and gross alterations in ovarian morphology. A wide range of ovarian morphologies were identified encompassing mild, such as an apparent reduction in follicle number, to moderate - ovarian atrophy with a complete absence of follicles, to severe - manifesting as normal ovarian structures replaced by benign ovarian tumours, including tubulostromal adenomas. Targeted gene expression profiling highlighted changes in RNA expression of molecules involved in processes such as steroidogenesis, gonadotropin signaling, transcriptional regulation, autocrine/paracrine signaling, cholesterol handling, and proprotein bioactivation. These results show that PCSK6 activity plays a role in maintaining normal cellular and tissue homeostasis in the ovary.
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Patiño LC et al. (2017) Is it possible to identify new mutations potentially associated with non-syndromic primary ovarian insufficiency (POI) via whole-exome sequencing (WES)? WES is an efficient tool to study genetic causes of POI as we have identified new mutations, some of which lead to protein destablization potentially contributing to the disease etiology. POI is a frequently occurring complex pathology leading to infertility. Mutations in only few candidate genes, mainly identified by Sanger sequencing, have been definitively related to the pathogenesis of the disease. This is a retrospective cohort study performed on 69 women affected by POI. WES and an innovative bioinformatics analysis were used on non-synonymous sequence variants in a subset of 420 selected POI candidate genes. Mutations in BMPR1B and GREM1 were modeled by using fragment molecular orbital analysis. Fifty-five coding variants in 49 genes potentially related to POI were identified in 33 out of 69 patients (48%). These genes participate in key biological processes in the ovary, such as meiosis, follicular development, granulosa cell differentiation/proliferation and ovulation. The presence of at least two mutations in distinct genes in 42% of the patients argued in favor of a polygenic nature of POI. It is possible that regulatory regions, not analyzed in the present study, carry further variants related to POI. WES and the in silico analyses presented here represent an efficient approach for mapping variants associated with POI etiology. Sequence variants presented here represents potential future genetic biomarkers. This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest.//////////////////