Aoran Huang,Jianyun Rao,Xin Feng,Xingru Li,Tianhua Xu,Li Yao
Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3′s interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets. 1. This study uses single-cell transcriptome to investigate vascular calcification in depth. 2. This study successfully identifies cellular heterogeneity related to vascular calcification. 3. This study reveals the crucial role of ID3 in vascular smooth muscle cell osteogenic differentiation. 4. In vivo and in vitro experiments of this study demonstrate the regulatory role of the USP1/ID3/E12/P21 axis in calcification. 5. This study provides potential molecular targets for the treatment of calcification-related diseases.
Anke Chen,Ning Fang,Zhifei Zhang,Yiqing Wen,Yajie Shen,Yanjie Zhang,Lu Zhang,Guoping Zhao,Jin Ding,Jixi Li
The global outbreak of Mpox, caused by the monkeypox virus (MPXV), has attracted international attention and become another major infectious disease event after COVID-19. The mRNA cap N7 methyltransferase (RNMT) of MPXV methylates the N7 position of the added guanosine to the 5'-cap structure of mRNAs and plays a vital role in evading host antiviral immunity. MPXV RNMT is composed of the large subunit E1 and the small subunit E12. How E1 and E12 of MPXV assembly remains unclear. Here, we report the crystal structures of E12, the MTase domain of E1 with E12 (E1CTD-E12) complex, and the E1CTD-E12-SAM ternary complex, revealing the detailed conformations of critical residues and the structural changes upon E12 binding to E1. Functional studies suggest that E1CTD N-terminal extension (Asp545-Arg562) and the small subunit E12 play an essential role in the binding process of SAM. Structural comparison of the AlphaFold2-predicted E1, E1CTD-E12 complex, and the homologous D1-D12 complex of vaccinia virus (VACV) indicates an allosteric activating effect of E1 in MPXV. Our findings provide the structural basis for the MTase activity stimulation of the E1-E12 complex and suggest a potential interface for screening the anti-poxvirus inhibitors.
危险品化学品经营许可证（带存储）