Q2 Abnormal Cullin1 neddylation-mediated p21 accumulation participates in the pathogenesis of recurrent spontaneous abortion by regulating trophoblast cell proliferation and differentiation
Q2 Abnormal Cullin1 neddylation-mediated p21 accumulation participates in the pathogenesis of recurrent spontaneous abortion by regulating trophoblast cell proliferation and differentiation
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Cullin1 neddylation异常介导的p21积累通过调节滋养层细胞增殖和分化参与复发性流产的发病机制
DOI：
10.1093/molehr/gaaa021
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发表时间：
2020-05-01
影响因子：
4
通讯作者：
Zhang, Songying
中科院分区：
文献类型：
--
作者：
Sun, Xiaohe;Tong, Xiaomei;Zhang, Songying
本研究旨在探讨neddylation在早期滋养细胞发育中的作用及其在复发性流产（RSA）发病机制中的变化。采用免疫荧光法和蛋白质印迹法检测NEDD 8蛋白在正常对照组和RSA患者早孕胎盘中的表达情况。Neddylated-cullin，尤其是Neddylated-cullin 1，下调，其底物p21在RSA样品中积累。在RSA胎盘的绒毛外滋养层（EVT）祖细胞中观察到NEDD 8细胞质募集。与临床样本的结果一致，在滋养层细胞系中使用MLN 4924抑制neddylation导致明显的p21蓄积和游离NEDD 8胞质募集。进一步的体外研究表明，neddylation抑制通过p21积累减弱Jeg-3细胞的增殖。此外，当滋养层干细胞（TS）来源于早期妊娠胎盘培养分化分析。MLN 4924通过下调HLA-G和GATA 3，损害TS细胞向EVT的分化。p21敲除可部分挽救MLN 4924抑制的HLA-G和GATA 3表达。总之，cullin 1 neddylation介导的p21降解是滋养层细胞增殖所必需的，并可通过影响HLA-G和GATA 3表达来影响滋养层细胞的可塑性。这些结果为RSA的病理机制和滋养细胞发育的生物学调控提供了新的见解。
The study explores the role of neddylation in early trophoblast development and its alteration during the pathogenesis of recurrent spontaneous abortion (RSA). Immunofluorescence and western blot were conducted to evaluate the expression pattern of NEDD8 protein in the first-trimester placentas of healthy control and RSA patients. Neddylated-cullins, especially neddylated-cullin1, were downregulated and their substrate, p21, was accumulated in RSA samples. NEDD8 cytoplasmic recruitment was observed in extravillous trophoblast (EVT) progenitors of RSA placentas. Consistent with the results of clinical samples, neddylation inhibition using MLN4924 in trophoblast cell lines caused obvious p21 accumulation and free NEDD8 cytoplasmic recruitment. Further in vitro study demonstrated neddylation inhibition attenuated proliferation of Jeg-3 cells via p21 accumulation. Moreover, when trophoblast stem (TS) cells derived from first-trimester placentas were cultured for differentiation analyses. MLN4924 impaired the differentiation of TS cells towards EVTs by downregulating HLA-G and GATA3. p21 knockdown could partly rescue MLN4924-suppressed HLA-G and GATA3 expression. In conclusion, cullin1 neddylation-mediated p21 degradation is required for trophoblast proliferation and can affect trophoblast plasticity by affecting HLA-G and GATA3 expression. The results provide insights into the pathological mechanism of RSA and the biological regulation of trophoblast development.