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Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase.

  • Kotla, Sivareddy1
  • Le, Nhat-Tu2
  • Vu, Hang Thi3
  • Ko, Kyung Ae3
  • Gi, Young Jin3
  • Thomas, Tamlyn N3
  • Giancursio, Carolyn3
  • Lusis, Aldos J4
  • Cooke, John P2
  • Fujiwara, Keigi3
  • Abe, Jun-Ichi5
  • 1 Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected]
  • 2 Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
  • 3 Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  • 5 Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected]
Published Article
Metabolism: clinical and experimental
Publication Date
Nov 01, 2019
DOI: 10.1016/j.metabol.2019.153962
PMID: 31476350


Disturbed flow (d-flow)-induced senescence and activation of endothelial cells (ECs) have been suggested to have critical roles in promoting atherosclerosis. Telomeric repeat-binding factor 2 (TERF2)-interacting protein (TERF2IP), a member of the shelterin complex at the telomere, regulates the senescence-associated secretory phenotype (SASP), in which EC activation and senescence are engendered simultaneously by p90RSK-induced phosphorylation of TERF2IP S205 and subsequent nuclear export of the TERF2IP-TERF2 complex. In this study, we investigated TERF2IP-dependent gene expression and its role in regulating d-flow-induced SASP. A principal component analysis and hierarchical clustering were used to identify genes whose expression is regulated by TERF2IP in ECs under d-flow conditions. Senescence was determined by reduced telomere length, increased p53 and p21 expression, and increased apoptosis; EC activation was detected by NF-κB activation and the expression of adhesion molecules. The involvement of TERF2IP S205 phosphorylation in d-flow-induced SASP was assessed by depletion of TERF2IP and mutation of the phosphorylation site. Our unbiased transcriptome analysis showed that TERF2IP caused alteration in the expression of a distinct set of genes, including rapamycin-insensitive companion of mTOR (RICTOR) and makorin-1 (MKRN1) ubiquitin E3 ligase, under d-flow conditions. In particular, both depletion of TERF2IP and overexpression of the TERF2IP S205A phosphorylation site mutant in ECs increased the d-flow and p90RSK-induced MKRN1 expression and subsequently inhibited apoptosis, telomere shortening, and NF-κB activation in ECs via suppression of p53, p21, and telomerase (TERT) induction. MKRN1 and RICTOR belong to a distinct reciprocal gene set that is both negatively and positively regulated by p90RSK. TERF2IP S205 phosphorylation, a downstream event of p90RSK activation, uniquely inhibits MKRN1 expression and contributes to EC activation and senescence, which are key events for atherogenesis. Copyright © 2019 Elsevier Inc. All rights reserved.

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