TGFBR3L is an inhibin B co-receptor that regulates female fertility

Abstract

Discovery of a novel pituitary protein suggests a new means to enhance fertility.

Screening and Preliminary Identification of Inhibin α Subunit-Specific Nanobodies by High-Throughput Sequencing Combined with Mass Spectrometry

“…It known that activin promotes the synthesis of Fshb mRNA in gonadotropin cells by forming ternary complexes with activin type II receptors and activin type I receptors [29,30], and activin has been proven to be the main driving force of FSH synthesis [31,32]. Inhibin prevents activin from exerting its biological function by competitively binding to the activin type II receptor after binding to the coreceptor (the coreceptor of inhibin A is TGFBR3 [33,34], and the coreceptor of inhibin B is TGFBR3L [35]), so as to indirectly inhibit the synthesis of FSH. When the nanobody has su cient a nity with the α-subunit, it can reduce the level of inhibin A (α subunit + βA subunit) and inhibin B (α subunit + βA subunit) by competitively binding to the α-subunit.…”

Efficacy of Immunization against a Novel Synthetic 13-Amino Acid Betaglycan-Binding Peptide Sequence of Inhibin α Subunit on Promoting Fertility in Female Rats

“…Both in vitro and in vivo studies evidenced that both inhibin A and inhibin B do not generate intracellular signals, and they mechanistically impair FSH biosynthesis by blocking activin signaling [ 3 , 7 ]. Activins are formed by homodimers or heterodimers of two inhibin β-subunits and potently stimulate FSH synthesis in pituitary gonadotrope cells through complexes of type II and I serine/threonine kinase receptors [ 1 ].…”

“…Subsequent studies further discovered that the binding of inhibin A and inhibin B to activin type II receptors requires the presence of their respective co-receptors [ 3 , 7 ]. Specifically, inhibin A antagonism of activins is dependent upon interactions with TGFβ type III receptor (TGFBR3, also known as betaglycan) [ 3 , 8 ], whereas inhibin B acts preferentially through an alternate transmembrane co-receptor, which is termed TGFβ receptor type III-like (TGFBR3L), to antagonize activin signaling [ 7 ].…”

“…Subsequent studies further discovered that the binding of inhibin A and inhibin B to activin type II receptors requires the presence of their respective co-receptors [ 3 , 7 ]. Specifically, inhibin A antagonism of activins is dependent upon interactions with TGFβ type III receptor (TGFBR3, also known as betaglycan) [ 3 , 8 ], whereas inhibin B acts preferentially through an alternate transmembrane co-receptor, which is termed TGFβ receptor type III-like (TGFBR3L), to antagonize activin signaling [ 7 ]. Betaglycan and TGFBR3L directly bind to inhibin A and B, respectively, and promote the formation of a stable high-affinity complex with activin type II receptors to competitively antagonize activin-mediated receptor activation and Fshb transcription [ 3 , 7 ].…”

“…Specifically, inhibin A antagonism of activins is dependent upon interactions with TGFβ type III receptor (TGFBR3, also known as betaglycan) [ 3 , 8 ], whereas inhibin B acts preferentially through an alternate transmembrane co-receptor, which is termed TGFβ receptor type III-like (TGFBR3L), to antagonize activin signaling [ 7 ]. Betaglycan and TGFBR3L directly bind to inhibin A and B, respectively, and promote the formation of a stable high-affinity complex with activin type II receptors to competitively antagonize activin-mediated receptor activation and Fshb transcription [ 3 , 7 ]. Conversely, mice with gonadotrope-specific betaglycan or knocked-out TGFBR3L were super-fertile, exhibiting increased folliculogenesis, numbers of ovulated eggs per cycle and litter sizes relative to controls [ 3 , 7 ].…”