Uterine serpin
Encyclopedia
Uterine serpins are members of the A clade of the serine proteinase inhibitor (serpin
) superfamily of protein
s and are encoded by the SERPINA14 gene
. Uterine serpins are produced by the uterine endometrium
of a restricted group of mammals under the influence of progesterone
or estrogen
. These proteins appear to be inactive proteinase inhibitors and may function during pregnancy
to regulate immune function or participate in transplacental transport.
uterine serpin was first identified because of its association with an iron-binding uterine protein termed uteroferrin. and was originally termed uteroferrin-associated protein.
The designation of uterine serpins as SERPINA14 is based on their classification as a highly-divergent group of the α1-antitrypsin or A clade. In other analyses, uterine serpins have been considered as a separate clade in the serpin superfamily.
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
) The uterine serpin gene is not expressed in all carnivores since the only uterine serpin identified in the cat
is a pseudogene. Examination of completed genomes indicates that uterine serpin genes do not exist in primates, mouse
, rat
, rabbit
, marsupials, platypus
, chicken
or zebrafish.
(Figure 1). Gene expression is limited to epithelial cells of endometrial glands. Late in pregnancy, uterine serpin protein can be found in the lumenal epithelium as well, perhaps as glandular epithelial cells move to the uterine lumen.
The major regulator of uterine serpin gene expression is progesterone. In the cow, estrogen can also increase uterine serpin gene expression.
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
.
. Uterine serpins from the sheep and pig are not inhibitory towards a variety of proteinases. In addition, several key amino acids in the hinge region of the reactive center loop which are important for proteinase inhibitory activity have not been conserved in uterine serpins. Bovine uterine serpin does inhibit pepsin
but probably through a mechanism distinct from the prototypical mechanism used by serpins.
placenta. Ovine uterine serpin also binds to activin
, IgM
and IgA
.
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.
Serpin
Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases .The first members of the serpin superfamily to be extensively...
) superfamily of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s and are encoded by the SERPINA14 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Uterine serpins are produced by the uterine endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
of a restricted group of mammals under the influence of progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
or estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
. These proteins appear to be inactive proteinase inhibitors and may function during pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
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. Termed uterine milk proteins (UTMP), their identification as members of the serpin superfamily was based on sequencing of the cDNA for the sheep gene. The pigPig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
uterine serpin was first identified because of its association with an iron-binding uterine protein termed uteroferrin. and was originally termed uteroferrin-associated protein.
The designation of uterine serpins as SERPINA14 is based on their classification as a highly-divergent group of the α1-antitrypsin or A clade. In other analyses, uterine serpins have been considered as a separate clade in the serpin superfamily.
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 LaurasiatheriaLaurasiatheria
Laurasiatheria is a large group of placental mammals believed to have originated on the northern supercontinent of Laurasia. It includes shrews, hedgehogs, pangolins, bats, whales, most hoofed mammals, and carnivorans, among others....
superorder of eutherian mammals. Among the clades in which uterine serpin genes exist are the Cetartiodactyla
Cetartiodactyla
Cetartiodactyla is the clade in which whales and even-toed ungulates have currently been placed. The term was coined by merging the name for the two orders, Cetacea and Artiodactyla, into a single word. The term Cetartiodactyla reflects the idea that whales evolved within the artiodactyls...
(dolphin
Dolphin
Dolphins are marine mammals that are closely related to whales and porpoises. There are almost forty species of dolphin in 17 genera. They vary in size from and , up to and . They are found worldwide, mostly in the shallower seas of the continental shelves, and are carnivores, mostly eating...
, cow, water buffalo
Water buffalo
The water buffalo is a domesticated bovid widely kept in Asia, Europe and South America.Water buffalo can also refer to:*Wild water buffalo , the wild ancestor of the domestic water buffalo...
, sheep, goat
Goat
The domestic goat is a subspecies of goat domesticated from the wild goat of southwest Asia and Eastern Europe. The goat is a member of the Bovidae family and is closely related to the sheep as both are in the goat-antelope subfamily Caprinae. There are over three hundred distinct breeds of...
, pig), Perissodactyla (horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...
) and some carnivores (dog
Dog
The domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...
, giant panda
Giant Panda
The giant panda, or panda is a bear native to central-western and south western China. It is easily recognized by its large, distinctive black patches around the eyes, over the ears, and across its round body. Though it belongs to the order Carnivora, the panda's diet is 99% bamboo...
) The uterine serpin gene is not expressed in all carnivores since the only uterine serpin identified in the cat
Cat
The cat , also known as the domestic cat or housecat to distinguish it from other felids and felines, is a small, usually furry, domesticated, carnivorous mammal that is valued by humans for its companionship and for its ability to hunt vermin and household pests...
is a pseudogene. Examination of completed genomes indicates that uterine serpin genes do not exist in primates, mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
, rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
, rabbit
Rabbit
Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...
, marsupials, platypus
Platypus
The platypus is a semi-aquatic mammal endemic to eastern Australia, including Tasmania. Together with the four species of echidna, it is one of the five extant species of monotremes, the only mammals that lay eggs instead of giving birth to live young...
, chicken
Chicken
The chicken is a domesticated fowl, a subspecies of the Red Junglefowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other species of bird...
or zebrafish.
Cellular expression and hormone regulation
Uterine serpins are products of the endometrial epitheliumEpithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
(Figure 1). Gene expression is limited to epithelial cells of endometrial glands. Late in pregnancy, uterine serpin protein can be found in the lumenal epithelium as well, perhaps as glandular epithelial cells move to the uterine lumen.
The major regulator of uterine serpin gene expression is progesterone. In the cow, estrogen can also increase uterine serpin gene expression.
In addition to expression in the endometrium, bovine uterine serpin is also expressed in the ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
(follicles, corpus luteum
Corpus luteum
The corpus luteum is a temporary endocrine structure in mammals, involved in production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A...
, and cumulus
Cumulus
Cumulus is a type of cloud with the appearance of a lump of cotton wool.Cumulus may also refer to:*Cumulus Media, a radio broadcasting company*Cumulus , digital asset management software developed by Canto Software*Reinhard Cumulus, glider...
-oocyte
Oocyte
An oocyte, ovocyte, or rarely ocyte, is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic...
complex) and by cotyledons of the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
.
Proteinase inhibitory activity
There are two lines of evidence to indicate that uterine serpins do not function as proteinase inhibitorsProtease inhibitor
Protease inhibitor can refer to:* Protease inhibitor : a class of medication that inhibits viral protease* Protease inhibitor : molecules that inhibit proteases...
. Uterine serpins from the sheep and pig are not inhibitory towards a variety of proteinases. In addition, several key amino acids in the hinge region of the reactive center loop which are important for proteinase inhibitory activity have not been conserved in uterine serpins. Bovine uterine serpin does inhibit pepsin
Pepsin
Pepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
but probably through a mechanism distinct from the prototypical mechanism used by serpins.
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. Uteroferrin is transferred across the placenta where it gives up its iron to fetal transferrin. Ovine uterine serpin binds pregnancy-associated glycoproteins, which are inactive aspartic proteinases secreted in large amounts by the ungulateUngulate
Ungulates are several groups of mammals, most of which use the tips of their toes, usually hoofed, to sustain their whole body weight while moving. They make up several orders of mammals, of which six to eight survive...
placenta. Ovine uterine serpin also binds to activin
Activin and inhibin
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle...
, IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
and IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
.
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
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
and natural killer cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
function in vitro and reduce natural-killer cell mediated abortion in a mouse model.