Nuclear translocation of cGAS orchestrates VEGF-A-mediated angiogenesis

• Published in: Cell reports (Cambridge) Vol. 42; no. 4; p. 112328
• Main Authors: Luo, Juanjuan, Lu, Chunjiao, Chen, Yang, Wu, Xuewei, Zhu, Chenchen, Cui, Wei, Yu, Shicang, Li, Ningning, Pan, Yihang, Zhao, Weijiang, Yang, Qingkai, Yang, Xiaojun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2023; Elsevier
• Subjects: angiogenesis; ARPC3; cGAS; CP: Cell biology; VEGF-A; VEGFR2; zebrafish; VEGFR2; CP: Cell biology; ARPC3; angiogenesis; cGAS; zebrafish; VEGF-A
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112328

Cyclic GMP-AMP synthase (cGAS) senses cytosolic incoming DNA and consequently activates stimulator of interferon response cGAMP interactor 1 (STING) to mount immune response. Here, we show nuclear cGAS could regulate VEGF-A-mediated angiogenesis in an immune-independent manner. We found VEGF-A stimulation induces cGAS nuclear translocation via importin-β pathway. Moreover, nuclear cGAS subsequently regulates miR-212-5p-ARPC3 cascade to modulate VEGF-A-mediated angiogenesis through affecting cytoskeletal dynamics and VEGFR2 trafficking from trans-Golgi network (TGN) to plasma membrane via a regulatory feedback loop. In contrast, cGAS deficiency remarkably impairs VEGF-A-mediated angiogenesis in vivo and in vitro. Furthermore, we found strong association between the expression of nuclear cGAS and VEGF-A, and the malignancy and prognosis in malignant glioma, suggesting that nuclear cGAS might play important roles in human pathology. Collectively, our findings illustrated the function of cGAS in angiogenesis other than immune surveillance, which might be a potential therapeutic target for pathological angiogenesis-related diseases. [Display omitted] •VEGF-A stimulation induces cGAS nuclear translocation via importin-β pathway•Nuclear cGAS modulates VEGF-A-mediated angiogenesis via regulating miR-212-5p-ARPC3 cascade•cGAS loss impairs trans-Golgi network-involved VEGFR2 trafficking•Nuclear translocation of cGAS is associated with human pathology Luo et al. illustrated the roles of nuclear cGAS in VEGF-A-mediated angiogenesis in vivo and in vitro. Nuclear cGAS is essential for VEGF-A-induced angiogenesis through affecting cell migration, cytoskeleton rearrangements, and VEGFR2 trafficking, which might contribute to the treatment of pathological angiogenesis-related diseases, such as cancer, and cardiovascular and eye diseases.