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PC6: A target for preventing pregnancy and HIV infection
Summary
Our studies suggest that PC6 is a novel target for the development of new female contraception which could also protect women from HIV infection. Our current research is developing various ways of inhibiting PC6 to prevent embryo implantation in models relevant to human implantation.
Description
Proprotein convertases (PCs) are a family of serine proteases that convert numerous important proteins from their initially synthesised non-active precursors into bioactive forms. PCs are hence important regulatory molecules in generating a large number of tissue-specific and functionally important bioactive proteins. These include growth factors, peptide hormones, adhesion molecules, and HIV envelope proteins. PCs are therefore regarded as promising targets for therapeutic applications.
We have discovered that PC6, one member of the PC family, is tightly regulated in the uterus during its preparation for receptivity and critical for implantation.
Preventing the production of PC6 in mice causes complete failure of implantation, while blocking PC6 function in human cells inhibits the equivalent critical step for implantation. What makes this discovery more important is that PCs including PC6 also play a critical role in HIV infection through the activation of HIV envelope proteins. This makes PC6 an exciting target for preventing pregnancy and HIV infection at the same time in women (a “double whammy” female contraceptive).
We are currently developing various ways to inhibit PC6 to prevent embryo implantation in vivo in models relevant to human implantation. We use a number of approaches, including biochemistry, molecular biology, cell culture, in vivo studies, drug discovery and development.
Funding
National Health and Medical Research Council
Contraceptive Research and Development Agency (CONRAD), USA
Outcomes
We have established that PC6 inhibitors can inhibit PC6 function in vitro and in cellular processes that are important for implantation.
We obtained promising results indicating that PC6 inhibitors can block embryo implantation in mice.
Selected Publications
Heng S, Hannan NJ, Rombauts L, Salamonsen LA, Nie G (2011) PC6 levels in uterine lavage are closely associated with uterine receptivity and significantly lower in a sub-group of women with unexplained infertility. Human Reprod [Jan 27, Epub ahead of print])
Heng S, Paule S, Hardman B, Li Y, Singh H, Rainczuk A, Stephens AN and Nie G (2010) Posttranslational activation of bone morphogenetic protein 2 is mediated by proprotein convertase 6 during decidualization for pregnancy establishment. Endocrinology, 151, 3909-3917
Nie G and Stephens AN (2010) A proteomic protocol to identify physiological substrates of proprotein convertases, Methods Mol Biol (in press, accepted in June 2010)
Paule S, Kilpatrick LM, Li Y, Stephens AN and Nie G (2010) A proteomic approach in identifying novel cytoskeletal remodelling proteins during decidualization of uterine stromal cells. J. Proteome Res, 9, 5739-4757
Kilpatrick LM, Stephens AN, Hardman BM, Salamonsen LA, Li Y, Stanton PG and Nie G (2009) Proteomic identification of caldesmon as a physiological substrate of proprotein convertase 6 in human uterine decidual cells essential for pregnancy establishment. J. Proteome Res 8, 4983-92
Nie G, Dimitriadis E, Hannan NJ, Paiva P and Salamonsen LA (2009) Local regulation of implantation at the human fetal-maternal interface. Int J Dev Biol 54, 313-322
Nie G, Kilpatrick LM, Stephens AN, Chen JC, Stanton P, and Salamonsen LA (2008). Proteomic identification of proprotein convertase 6 substrates in human endometrial stromal cells during decidualization. Biol Reprod 2008; 78:p57
Freyer C, Kilpatrtick L, Salamonsen LA and Nie G (2007) Pro-protein convertases other than PC6 are not tightly regulated for implantation in the human endometrium. Reprod 133, 1189-1197.
Nie G (2006) Proprotein convertase 6: a key uterine regulator for implantation. Japan Society of Fertilization and Implantation, suppl issue: p77-78.
Okada H, Nie G, Salamonsen LA (2005) Requirement for proprotein convertase 5/6 during decidualization of human endometrial stromal cells in vitro. J Clin Endocrinol Metab 90: 1028-1034.
Nie G, Li Y, Wang M, Liu YX, Findlay JK, Salamonsen LA (2005) Inhibiting uterine proprotein convertase 6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility. Biol Reprod 72: 1029-1036.
Nie G, Li Y, Minoura H, Findlay JK, Salamonsen LA (2003) Specific and transient up-regulation of proprotein convertase 6 (PC6) at the site of embryo implantation and identification of a uterine-specific transcript in mouse uterus during early pregnancy. Biol Reprod 68: 439-447.