Uterine serpin

Last updated
Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 14
Identifiers
Organism Bos taurus (domestic cow)
SymbolSERPINA14
Entrez 286871
RefSeq (mRNA) NM_174797
RefSeq (Prot) NP_777222
UniProt P46201
Other data
Chromosome 21: 59.39 - 59.4 Mb
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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]

Figure 1. Immunohistochemical localization of uterine serpin in endometrial glands of an ovariectomized ewe treated with progesterone for 60 days. Uterine serpin localized to endometrial glands in the sheep uterus.jpg
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]

See also

Related Research Articles

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The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer thickens and then is shed during menstruation in humans and some other mammals, including other apes, Old World monkeys, some species of bat, the elephant shrew and the Cairo spiny mouse. In most other mammals, the endometrium is reabsorbed in the estrous cycle. During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus. The speculated presence of an endometrial microbiota has been argued against.

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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. doi: 10.1016/S0021-9258(18)94076-7 . 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. doi: 10.1016/S0021-9258(18)67173-X . 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. S2CID   9248169.
  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. Bibcode:2000JEZ...288..165P. 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/endo.136.2.7835310. 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. Bibcode:1996PNAS...9313653M. doi: 10.1073/pnas.93.24.13653 . PMC   19381 . 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. doi: 10.1016/S0021-9258(19)68096-8 . 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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