HLA- C expression in extravillous trophoblasts is determined by an ELF3-NLRP2/NLRP7 regulatory axis

• 成果类型: Article
• 署名作者: Gu, Bowen; Le, Gia-Han; Herrera, Sebastian; Blair, Steven J.; Meissner, Torsten B.; Strominger, Jack L.
• 署名单位: Harvard University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12805
• DOI: 10.1073/pnas.2404229121
• 发表日期: 2024-07-30
• 关键词: nf-kappa-b; nucleotide-binding; differentiation; interface; FAMILY; genes; nlrc5; nlrp2

摘要

The distinct human leukocyte antigen (HLA) class I expression pattern of human extravillous trophoblasts (EVT) endows them with unique tolerogenic properties that enable successful pregnancy. Nevertheless, how this process is elaborately regulated remains elusive. Previously, E74 like ETS transcription factor 3 (ELF3) was identified to govern high- level HLA- C expression in EVT. In the present study, ELF3 is found to bind to the enhancer region of two adjacent NOD- like receptor (NLR) genes, NLR family pyrin domain- containing 2 and 7 (NLRP2, NLRP7). Notably, our analysis of ELF3- deficient JEG- 3 cells, a human choriocarcinoma cell line widely used to study EVT biology, suggests that ELF3 transactivates NLRP7 while suppressing the expression of NLRP2. Moreover, we find that NLRP2 and NLRP7 have opposing effects on interface. We confirmed that NLRP2 suppresses HLA- C levels and described a unique role for NLRP7 in promoting HLA- C expression in JEG- 3. These results suggest that these two NLR genes, which arose via gene duplication in primates, are fine- tuned by in EVT, presumably through modulating the degradation kinetics of IkB alpha. Targeting pregnancy- related disorders, such as recurrent hydatidiform moles and fetal growth restriction, and thus improve placental development and pregnancy outcomes.