Follistatin

Synthesis and release

FSH and forskolin stimulate follistatin synthesis in rat granulosa cells. Follistatin synthesis in the rat anterior pituitary is stimulated by activin via Smad proteins and by the gonadotropin-releasing hormone (GnRH) via cAMP signaling. Dexamethasone upregulates follistatin gene expression in osteoblasts. The peroxisome proliferator-activated receptor (PPAR) γ downregulates follistatin gene expression in intestinal epithelial cells. In the zebrafish, oocyte-derived bone morphogenetic protein (BMP) stimulates follistatin production from ovarian follicle cells. In the carp pituitary, activin stimulates follistatin production, but dopaminergic input from the hypothalamus inhibits follistatin production.

Biological functions

Follistatin 288 antagonizes the effects of activins in various cells and tissues by blocking the binding of activin to their receptors. The exact functions of follistatin 315 and follistatin-like 3 have not yet been clarified. Follistatin also binds several members of the transforming growth factor (TGF) β family, including myostatin and several BMPs. Mice in which the follistatin gene was inactivated do not survive long after birth due to a variety of skeletal and cutaneous abnormalities. Overexpression of the follistatin gene resulted in the degeneration of seminiferous tubules in male mice and defects in follicular development in female mice, when the mice show the highest levels of follistatin expression. Granulosa cell-specific inactivation of the follistatin gene results in reduced numbers of ovarian follicles and ovulation and elevated levels of FSH in mice. Follistatin-like 3 knockout mice exhibited increased pancreatic islet size, enhanced circulating insulin levels, and improved glucose tolerance.

Clinical implications

Patients with septicemia show high serum concentrations of follistatin and activin. The exposure of bacterial lipopolysaccharide induces an elevation in serum follistatin concentration in response to a rapid increase in the circulating activin A. Activin A promotes the release of inflammatory cytokines such as TNF and IL-1, whereas follistatin is able to suppress the release of these cytokines. Serum levels of follistatin increased in patients with acute liver failure.

Description

Follistatin is a single-chain glycoprotein structurally unrelated to the inhibin and activin proteins. Follistatin binds activin and neutralizes activin action. Follistatin was originally isolated from porcine and bovine follicular fluid for its ability to suppress folliclestimulating hormone (FSH) secretion from the rat pituitary. Subsequently, it was discovered that follistatin binds activin with high affinity.

Physical properties

Mr 35,000 (follistatin 315), 32,000 (follistatin 288). pI 5.0–6.0 (follistatin 315), 8.0–9.0 (follistatin 288). Soluble in water.

Structure and conformation

There are three alternatively spliced products of the single follistatin gene: follistatin 288, follistatin 303, and follistatin 315. Follistatin 288 lacks the carboxyl-terminal Glurich acidic region of follistatin 315. Follistatin 303 is produced by the proteolysis of follistatin 315. Follistatins have two N-linked glycosylation sites, producing different size variants. Follistatins 288 and 315 contain three cysteine-rich follistatin domains of 73–77 aa residues and have a similar binding affinity for activin. Both follistatins have a biding site for heparin and heparan sulfate, a major component of proteoglycans on the cell surface. Follistatin 288 shows high affinity for heparan sulfate and is membrane-bound while follistatin 315 has low affinity for cell-surface proteoglycans and is the predominant form in circulation. Additionally, follistatin-like 3 (follistatin-related protein, FSTL3) consists of two follistatin domains, but lacks the heparin binding site. Two follistatin molecules bind one activin molecule via the activin β-subunits.