Abstract 417: Trf2-Interacting Protein (Terf2ip) S205 Phosphorylation Mediates Atherosclerosis via Orchestrating Endothelial Senescence and Inflammation

Abstract

Telomeric repeat-binding factor 2 (TRF2)-interacting protein (TERF2IP) S205 phosphorylation mediates atherosclerosis (AS) via orchestrating endothelial cell (EC) senescence (Sen) and inflammation. Nhat-Tu Le, Kyung-Sun Heo, Kyung Ae Ko, Yunting Tao,Tamlyn Thomas, Raymundo A Quintana Quezada, Keigi Fujiwara, and Jun-ichi Abe Department of Cardiology, UT MD Anderson Cancer Center Objective: Shortened telomere (TL) provokes EC Sen, which is associated with focalized EC inflammation and plaque formation in arteries exposed by disturbed blood flow (d-flow). Although d-flow is known to increase both EC inflammation and Sen, the exact mechanism by which d-flow induces these two different EC pathologies and subsequent AS is poorly understood. Methods & Results: TERF2IP, as a member of the sheltrin complex, is not only crucial for DNA double strand break repair at the TL, but also for activation of cytosolic IkB kinase (IKK) and subsequent NF-kB activity. TERF2IP and TRF2 form a stable heterodimer to protect the duplex region of TLs, while activating NF-kB, especially under the d-flow condition. We have discovered that inhibition of p90RSK reduces d-flow-induced EC Sen and inflammation via down-regulating TERF2IP S205 phosphorylation. The nuclear TERF2IP-TRF2 complex protects TLs by repairing DNA damages while the cytosolic complex plays a role in NF-kB activation. When we mutated the TERF2IP phosphorylation site (S205A) in ECs, the nuclear export of the TERF2IP-TRF2 complex was abolished, which inhibited d-flow-induced NF-kB activation and Sen. Both the depletion of TERF2IP by siRNA and S205A mutation inhibited d-flow-induced TERF2 nuclear export, and residual TRF2 at the TL inhibited d-flow-induced TL dysfunction. The mutation of TERF2IP S205A inhibited cytosolic IKK-NF-kB activation by eliminating the cytosolic TERF2IP-TERF2 complex. The inhibition of d-flow-induced inflammatory adhesion molecule expression and consequent AS were also confirmed in EC-specific TERF2IP knock out mice. Conclusion: These results suggest that S205 phosphorylation of TERF2IP induced by p90RSK activation is required for d-flow-induced TL shortening and NF-kB activation via regulating nuclear export of the TERF2IP-TERF2 complex.