Translational regulation of SND1 governs endothelial homeostasis during stress

• Published in: The Journal of clinical investigation 2025-02, Vol.135 (3), p.1-17
• Main Authors: Han, Zhenbo, Yan, Gege, Jousma, Jordan, Nukala, Sarath Babu, Amiri, Mehdi, Kiniry, Stephen, Tabatabaei, Negar, Kwon, Youjeong, Zhang, Sen, Rehman, Jalees, Pinho, Sandra, Ong, Sang-Bing, Baranov, Pavel V, Tahmasebi, Soroush, Ong, Sang-Ging
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Cancer therapies; Cardiovascular diseases; Cardiovascular system; Cell Cycle Proteins; Cytotoxicity; DNA damage; DNA repair; Drug dosages; Endonucleases - genetics; Endonucleases - metabolism; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Enzymes; Gene expression; Homeostasis; Humans; Kinases; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mortality; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pluripotency; Protein Biosynthesis - drug effects; Proteins; Proteomes; Ribonucleic acid; RNA; Stem cells; Stress, Physiological; Sunitinib - pharmacology; Toxicity; Translation; Tumors; Tyrosine kinase inhibitors; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Wound healing
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI168730

Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell-derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain-containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.