Uterine serpin

Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 14
Identifiers
Organism Bos taurus (domestic cow)
Symbol SERPINA14
Entrez 286871
RefSeq (mRNA) NM_174797
RefSeq (Prot) NP_777222
UniProt P46201
Other data
Chromosome 21: 59.39 - 59.4 Mb

Uterine serpins are members of the A clade of the serine protease inhibitor (serpin) superfamily of proteins and are encoded by the SERPINA14 gene. Uterine serpins are produced by the endometrium of a restricted group of mammals under the influence of progesterone or estrogen. These proteins appear to be inactive protease inhibitors and may function during pregnancy to regulate immune function or participate in transplacental transport.

Nomenclature

Uterine serpins were originally described in the uterine secretions of unilaterally-pregnant sheep as a pair of 57 kDa and 55 kDa glycoproteins.[1] Termed uterine milk proteins, their identification as members of the serpin superfamily was based on sequencing of the cDNA for the sheep gene.[2] The pig uterine serpin was first identified because of its association with an iron-binding uterine protein termed uteroferrin.[3][4] and was originally termed uteroferrin-associated protein.[5]

The designation of uterine serpins as SERPINA14[6] is based on their classification as a highly-divergent group of the α1-antitrypsin or A clade.[7] In other analyses, uterine serpins have been considered as a separate clade in the serpin superfamily.[8]

Evolution

The uterine serpins are novel with respect to other serpins by virtue of their limited distribution among mammals. They have been described only in species of the Laurasiatheria superorder of eutherian mammals. Among the clades in which uterine serpin genes exist are the Cetartiodactyla (dolphin, cow, water buffalo, sheep, goat, pig), Perissodactyla (horse) and some carnivores (dog, giant panda)[6][9] The uterine serpin gene is not expressed in all carnivores since the only uterine serpin identified in the cat is a pseudogene.[6] Examination of completed genomes indicates that uterine serpin genes do not exist in primates, mouse, rat, rabbit, marsupials, platypus, chicken or zebrafish.[6][10]

Localization of ovine uterine serpin in endometrial glands.
Figure 1. Immunohistochemical localization of uterine serpin in endometrial glands of an ovariectomized ewe treated with progesterone for 60 days.

Cellular expression and hormone regulation

Uterine serpins are products of the endometrial epithelium (Figure 1). Gene expression is limited to epithelial cells of endometrial glands.[11] Late in pregnancy, uterine serpin protein can be found in the lumenal epithelium as well,[12] perhaps as glandular epithelial cells move to the uterine lumen.

The major regulator of uterine serpin gene expression is progesterone.[6] In the cow, estrogen can also increase uterine serpin gene expression.[13][14]

In addition to expression in the endometrium, bovine uterine serpin is also expressed in the ovary (follicles, corpus luteum, and cumulus-oocyte complex) and by cotyledons of the placenta.[14][15]

Protease inhibitory activity

There are two lines of evidence to indicate that uterine serpins do not function as protease inhibitors. Uterine serpins from the sheep and pig are not inhibitory towards a variety of proteases.[2][5][16][17] In addition, several key amino acids in the hinge region of the reactive center loop which are important for protease inhibitory activity have not been conserved in uterine serpins.[6] Bovine uterine serpin does inhibit pepsin but probably through a mechanism distinct from the prototypical mechanism used by serpins.[17]

Function during pregnancy

There are two possible biological roles for uterine serpins during pregnancy. The first is as a binding protein. Porcine uterine serpin binds non-covalently to uteroferrin in a way that stabilizes the iron-binding capacity of uteroferrin.[4] Uteroferrin is transferred across the placenta where it gives up its iron to fetal transferrin.[18] Ovine uterine serpin binds pregnancy-associated glycoproteins,[17] which are inactive aspartic proteases secreted in large amounts by the ungulate placenta.[19] Ovine uterine serpin also binds to activin,[20] IgM and IgA.[21]

Another possible role for uterine serpins is in the inhibition of immune cell proliferation during pregnancy to provide protection for the allogeneically-distinct conceptus. In particular, sheep uterine serpin can inhibit lymphocyte and natural killer cell function in vitro and reduce natural-killer cell mediated abortion in a mouse model.[22]

Genetics

A single nucleotide polymorphism at position 1269 of the bovine uterine serpin gene has been associated with productive life[23] in cattle populations.[15]

References

  1. ↑ Moffatt J, Bazer FW, Hansen PJ, Chun PW, Roberts RM (March 1987). "Purification, secretion and immunocytochemical localization of the uterine milk proteins, major progesterone-induced proteins in uterine secretions of the sheep". Biol. Reprod. 36 (2): 419–30. doi:10.1095/biolreprod36.2.419. PMID 3580461.
  2. 1 2 Ing NH, Roberts RM (February 1989). "The major progesterone-modulated proteins secreted into the sheep uterus are members of the serpin superfamily of serine protease inhibitors". J. Biol. Chem. 264 (6): 3372–9. PMID 2464597.
  3. ↑ Ibelgaufts H (2002-01-01). "Uteroferrin". Cytokines & Cells Encyclopedia - COPE. Retrieved 2010-12-02.
  4. 1 2 Baumbach GA, Ketcham CM, Richardson DE, Bazer FW, Roberts RM (September 1986). "Isolation and characterization of a high molecular weight stable pink form of uteroferrin from uterine secretions and allantoic fluid of pigs". J. Biol. Chem. 261 (27): 12869–78. PMID 3017991.
  5. 1 2 Malathy PV, Imakawa K, Simmen RC, Roberts RM (March 1990). "Molecular cloning of the uteroferrin-associated protein, a major progesterone-induced serpin secreted by the porcine uterus, and the expression of its mRNA during pregnancy". Mol. Endocrinol. 4 (3): 428–40. doi:10.1210/mend-4-3-428. PMID 2342477.
  6. 1 2 3 4 5 6 Padua MB, Kowalski AA, Cañas MY, Hansen PJ (February 2010). "The molecular phylogeny of uterine serpins and its relationship to evolution of placentation". FASEB J. 24 (2): 526–37. doi:10.1096/fj.09-138453. PMID 19825977.
  7. ↑ Irving JA, Pike RN, Lesk AM, Whisstock JC (December 2000). "Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function". Genome Res. 10 (12): 1845–64. doi:10.1101/gr.GR-1478R. PMID 11116082.
  8. ↑ Peltier MR, Raley LC, Liberles DA, Benner SA, Hansen PJ (August 2000). "Evolutionary history of the uterine serpins". J. Exp. Zool. 288 (2): 165–74. doi:10.1002/1097-010X(20000815)288:2<165::AID-JEZ7>3.0.CO;2-R. PMID 10931499.
  9. ↑ Padua MB, Hansen PJ (October 2010). "Evolution and function of the uterine serpins (SERPINA14)". Am. J. Reprod. Immunol. 64 (4): 265–74. doi:10.1111/j.1600-0897.2010.00901.x. PMID 20678169.
  10. ↑ van Gent D, Sharp P, Morgan K, Kalsheker N (November 2003). "Serpins: structure, function and molecular evolution". Int. J. Biochem. Cell Biol. 35 (11): 1536–47. doi:10.1016/S1357-2725(03)00134-1. PMID 12824063.
  11. ↑ Stewart MD, Johnson GA, Gray CA, et al. (June 2000). "Prolactin receptor and uterine milk protein expression in the ovine endometrium during the estrous cycle and pregnancy". Biol. Reprod. 62 (6): 1779–89. doi:10.1095/biolreprod62.6.1779. PMID 10819783.
  12. ↑ Stephenson DC, Leslie MV, Low BG, Newton GR, Hansen PJ, Bazer FW (October 1989). "Secretion of the major progesterone-induced proteins of the sheep uterus by caruncular and intercaruncular endometrium of the pregnant ewe from days 20-140 of gestation". Domest. Anim. Endocrinol. 6 (4): 349–62. doi:10.1016/0739-7240(89)90029-5. PMID 2620505.
  13. ↑ Bauersachs S, Ulbrich SE, Gross K, et al. (June 2005). "Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes". J. Mol. Endocrinol. 34 (3): 889–908. doi:10.1677/jme.1.01799. PMID 15956356.
  14. 1 2 Ulbrich SE, Frohlich T, Schulke K, et al. (October 2009). "Evidence for estrogen-dependent uterine serpin (SERPINA14) expression during estrus in the bovine endometrial glandular epithelium and lumen". Biol. Reprod. 81 (4): 795–805. doi:10.1095/biolreprod.108.075184. PMID 19494250.
  15. 1 2 Khatib H, Schutzkus V, Chang YM, Rosa GJ (May 2007). "Pattern of expression of the uterine milk protein gene and its association with productive life in dairy cattle". J. Dairy Sci. 90 (5): 2427–33. doi:10.3168/jds.2006-722. PMID 17430947.
  16. ↑ Liu WJ, Hansen PJ (February 1995). "Progesterone-induced secretion of dipeptidyl peptidase-IV (cluster differentiation antigen-26) by the uterine endometrium of the ewe and cow that costimulates lymphocyte proliferation". Endocrinology. 136 (2): 779–87. doi:10.1210/en.136.2.779. PMID 7835310.
  17. 1 2 3 Mathialagan N, Hansen TR (November 1996). "Pepsin-inhibitory activity of the uterine serpins". Proc. Natl. Acad. Sci. U.S.A. 93 (24): 13653–8. doi:10.1073/pnas.93.24.13653. PMC 19381Freely accessible. PMID 8942989.
  18. ↑ Buhi WC, Ducsay CA, Bazer FW, Roberts RM (February 1982). "Iron transfer between the purple phosphatase uteroferrin and transferrin and its possible role in iron metabolism of the fetal pig". J. Biol. Chem. 257 (4): 1712–23. PMID 7056739.
  19. ↑ Green JA, Xie S, Roberts RM (January 1998). "Pepsin-related molecules secreted by trophoblast". Rev. Reprod. 3 (1): 62–9. doi:10.1530/ror.0.0030062. PMID 9509990.
  20. ↑ McFarlane JR, Foulds LM, O'Connor AE, et al. (October 1999). "Uterine milk protein, a novel activin-binding protein, is present in ovine allantoic fluid". Endocrinology. 140 (10): 4745–52. doi:10.1210/en.140.10.4745. PMID 10499534.
  21. ↑ Hansen PJ, Newton GR (January 1988). "Binding of immunoglobulins to the major progesterone-induced proteins secreted by the sheep uterus". Arch. Biochem. Biophys. 260 (1): 208–17. doi:10.1016/0003-9861(88)90442-0. PMID 3341741.
  22. ↑ Hansen PJ (October 1998). "Regulation of uterine immune function by progesterone--lessons from the sheep". J. Reprod. Immunol. 40 (1): 63–79. doi:10.1016/S0165-0378(98)00035-7. PMID 9862257.
  23. ↑ Schutz M. "Using Net Merit To Select Dairy Bulls". Purdue University. Retrieved 2010-12-02.
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