Localization of Ubiquitin and Ubiquitin Cross-Reactive Protein in Human and Baboon Endometrium and Decidua during the Menstrual Cycle and Early Pregnancy1

Bebington, C.; Bell, Steven; Doherty, Fergus J.; Fazleabas, Asgerally T.; Fleming, Steven D.

doi:10.1095/biolreprod60.4.920

Cited by 65 publications

(46 citation statements)

References 36 publications

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“…The biological consequences of ISG15 modification or its association with these proteins is unclear. Previous immunofluorescence and biochemical studies have shown that ISG15 and its conjugates can be located on the cytoskeleton (31)(32)(33). One possible mechanism could be to move IFN-induced proteins from their normal location to the cytoskeleton, where they exert their antiviral activity by inhibiting either the trafficking of viral proteins or the exocytosis of viral particles.…”

Section: Discussionmentioning

confidence: 99%

HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets

Wong

Pung²,

Sze³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

246

232

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Type I IFNs induce the expression of IFN-stimulated gene 15 (ISG15)and its conjugation to cellular targets. ISGylation is a multistep process involving IFN-inducible Ube1L, UbcH8, and a yet-to-be identified E3 ligase. Here we report the identification of an IFNinduced HECT-type E3 protein ligase, HERC5͞Ceb1, which mediates ISGylation. We also defined a number of proteins modified by ISG15 after IFN triggering or HERC5 overexpression. A reduction in endogenous HERC5 by small interfering RNA inhibition blocks the IFN-induced ISG15 conjugation. Conversely, HERC5 coexpression with Ube1L and UbcH8 induces the ISG15 conjugation in vivo independent of IFN stimulation. A targeted substitution of Cys-994 to Ala in the HECT domain of HERC5 completely abrogates its E3 protein ligase activity. Therefore, this study demonstrates that HERC5͞Ceb1 is involved in the conjugation of ISG15 to cellular proteins.ISG15 ͉ Ceb1 ͉ innate immunity ͉ antiviral proteins T ype I IFNs (IFN-␣͞␤) play an essential role in both innate antiviral and adaptive immune responses and are rapidly produced in response to microbial infection (1-3). They exert signals through the activation of the Janus kinase-signal transducer and activator of transcription pathway that mediates rapid induction of IFN-stimulated genes (ISGs) (4, 5). ISG15 is one of the most strongly induced genes after IFN treatment (6, 7) and is also significantly induced by viral infection (8, 9) and LPS treatment (10, 11). The ISG15 protein starts with two ubiquitin-related domains that have Ϸ27% sequence identity to ubiquitin and terminate in a conserved 152 LRLRGG 157 ubiquitin C-terminal motif. This study suggests that ISG15 could act in a similar way to ubiquitin and other ubiquitin-like proteins such as SUMO by forming an isopeptide bond with cellular proteins (6, 12, 13). The crystal structure of ISG15 revealed that ISG15 consists of two domains with ubiquitinlike folds joined by a linker sequence (14).Conjugation of ISG15 to cellular proteins occurs in a parallel but distinct mechanism to that of ubiquitin (15-17). The E1 enzyme for ISG15, Ube1L, is a single-subunit enzyme and is identified in vitro by its ability to catalyze the formation of a thioester bond between ISG15 and Ube1L (17,18). The Ube1L protein is highly similar to the E1 enzyme for ubiquitin at the protein level. However, this protein does not form a conjugate with ubiquitin, indicating that Ube1L is an E1 enzyme for the ISG15 conjugation system (ISGylation). Influenza B virus blocks protein ISGylation by inhibiting the activation step through the interaction of the NS1B viral protein with ISG15 (18). This finding was the first suggestion that ISGylation might be important for protecting cells from viral infection.Two groups recently found that a member of the ubiquitin E2-conjugating enzyme family, UbcH8, is involved in the ISGylation (19,20). Like ISG15 and Ube1L, the expression of UbcH8 is also induced by IFN (21). The suppression of UbcH8 protein expression by RNA interference is shown to dramatically inhib...

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Section: Discussionmentioning

confidence: 99%

HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets

Wong

Pung²,

Sze³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

246

232

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“…In the recent years, increasing observations have demonstrated the role of ubiquitin system in reproductive processes, such as gametogenesis, modulation of steroid receptor concentrations, placental development and endo-metrial modification at the beginning of pregnancy [31]. These wide-range effects have led to extensive research and several studies recently demonstrated the increase of ubiquitylation in the uterus during embryo implantation; thus, the proper control and turnover of this key signaling protein activity suggest potential roles in controlling critical aspects of implantation [32][33][34][35]. This is also emphasized by the observation that ubiquitin is accumulated in trophoblast of expanding blastocysts [36], suggesting that dysregulation of ubiquitin system may be responsible for failure IVF outcome.…”

Section: Discussionmentioning

confidence: 99%

“…All consenting patients undergoing fertility treatment at the Humanitas Fertility Center, Humanitas Research Hospital, Rozzano, Italy, with supernumerary blastocysts were included in the study irrespective of the woman's age (range years [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41], infertility diagnosis (female or male), ovarian stimulation protocol (use of GnRH agonist or antagonist protocols in combination with recombinant and/or highly purified urinary gonadotropins), or performance of standard IVF or intracytoplasmic sperm injection (ICSI). The study was part of a trial on blastocoel fluid collection in order to test the safety of this procedure on pregnancy outcome [22].…”

Section: Patient Populationmentioning

confidence: 99%

Proteomic profile of maternal-aged blastocoel fluid suggests a novel role for ubiquitin system in blastocyst quality

Tedeschi

Albani

Borroni

et al. 2016

J Assist Reprod Genet

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Purpose The etiology of maternal aging, a common cause of female factor infertility and a rate-limiting step in vitro fertilization (IVF) success, remains still unclear. Proteomic changes responsible for the impaired successful pregnancy outcome after IVF with aged blastocysts have not been yet evaluated. The objective of this prospective study was to employ proteomic techniques and bioinformatic tools to enlight differences at the protein level in blastocoel fluid of aged and younger woman. Methods Protein composition of human blastocoel fluid isolated by micromanipulation from 46 blastocysts of women aged <37 years (group A) and 29 of women aged ≥37 years (group B) have been identified by a shotgun proteomic approach based on high-resolution nano-liquid chromatography electrospray-ionization-tandem mass spectrometry (nLC-ESI-MS/MS) using label free for the relative quantification of their expression levels. Results The proteomic analysis leads to the identification and quantification of 148 proteins; 132 and 116 proteins were identified in groups A and B, respectively. Interestingly, the identified proteins are mainly involved in processes aimed at fine tuning embryo implantation and development. Among the 100 proteins commonly expressed in both groups, 17 proteins are upregulated and 44 downregulated in group B compared to group A. Overall, the analysis identified 33 proteins, which were increased or present only in B while 76 were decreased in B or present only in A. Conclusions Data revealed that maternal aging mainly affects blastocyst survival and implantation through unbalancing the equilibrium of the ubiquitin system known to play a crucial role in fine-tuning several aspects required to ensure successful pregnancy outcome.

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“…Numerous studies in mice, primates, and humans have shown that matrix metalloproteinases (MMPs), which are responsible for degrading the ECM, are key regulators of blastocyst implantation [19][20][21]. Ubiquitin-related proteins were shown to be present in human, baboon, rhesus monkey, cow, sheep, and mouse pregnant uteri [22][23][24][25][26], and may be essential for endometrial modification and placental development during early pregnancy. However, no direct evidence has show whether the UPP is involved in embryo implantation or has a regulatory effect on mRNA expression and the activities of MMP-2 and MMP-9.…”

Section: Biological Significance Of Lmp2/β β β β1i In Embryo Implantamentioning

confidence: 99%

The Proteasome Subunit LMP2/b1i In the Female Genital System

Hayashi¹

2013

JGO

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Abstract:Protein degradation by the ubiquitin-proteasome system is central to cell homeostasis and survival. Defects in this process are associated with diseases such as cancer and neurodegenerative disorders. The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven α subunits, and the two central rings are each formed by seven β1 subunits. Replacement of LMPY by LMP2/β1i increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. LMP2/β1i mediates the cell survival pathway. Embryo implantation involves the invasion of placental extravillous trophoblast cells (EVTs) into the uterus. Normal human placentas or placentas from hydatidiform mole patients were collected and the expression of LMP2/β1i in different cell types including trophoblastic column (TC), cytotrophoblast cells (CTB) and syncytiotrophoblasts (STBs) was examined under different pathological states by pathological analysis. LMP2/β1i expression in TC of partial hydatidiform mole and complete hydatidiform mole placentas was higher than that in TC of normal human placentas. The overexpression of LMP2/β1i in trophoblast cells of hydatidiform moles may contribute to its highly invasive phenotype. LMP2/β1i-deficient mice reportedly exhibit uterine neoplasms, with a disease prevalence of 36% by 12 months of age. Further experiments with human and mouse uterine tissues clarified the biological significance of LMP2/β1i in malignant myometrium transformation and the cell cycle, which implicated LMP2/β1i as an anti-tumorigenic candidate. In this mini review, we covered recent insights into the molecular and cellular pathways involved in LMP2/β1i-mediated biological functions, with a particular focus on embryo implantation and uterine mesenchymal tumorigenesis.

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Localization of Ubiquitin and Ubiquitin Cross-Reactive Protein in Human and Baboon Endometrium and Decidua during the Menstrual Cycle and Early Pregnancy1

Cited by 65 publications

References 36 publications

HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets

HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets

Proteomic profile of maternal-aged blastocoel fluid suggests a novel role for ubiquitin system in blastocyst quality

The Proteasome Subunit LMP2/b1i In the Female Genital System

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