Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein

Research output: Contribution to journalArticle

Sivareddy Kotla, Hang Thi Vu, Kyung Ae Ko, Yin Wang, Masaki Imanishi, Kyung-Sun Heo, Yuka Fujii, Tamlyn N. Thomas, Young Jin Gi, Hira Mazhar, Jesus Paez-Mayorga, Ji-Hyun Shin, Yunting Tao, Carolyn J. Giancursio, Jan L.M. Medina, Jack Taunton, Aldos J. Lusis, John P. Cooke, Keigi Fujiwara, Nhat-Tu Le & 1 others Jun-ichi Abe

The interplay among signaling events for endothelial cell (EC) senescence, apoptosis, and activation and how these pathological conditions promote atherosclerosis in the area exposed to disturbed flow (d-flow) in concert remain unclear. The aim of this study was to determine whether telomeric repeat-binding factor 2–interacting protein (TERF2IP), a member of the shelterin complex at the telomere, can regulate EC senescence, apoptosis, and activation simultaneously, and if so, by what molecular mechanisms. We found that d-flow induced p90RSK and TERF2IP interaction in a p90RSK kinase activity–dependent manner. An in vitro kinase assay revealed that p90RSK directly phosphorylated TERF2IP at the serine 205 (S205) residue, and d-flow increased TERF2IP S205 phosphorylation as well as EC senescence, apoptosis, and activation by activating p90RSK. TERF2IP phosphorylation was crucial for nuclear export of the TERF2IP-TRF2 complex, which led to EC activation by cytosolic TERF2IP-mediated NF-κB activation and also to senescence and apoptosis of ECs by depleting TRF2 from the nucleus. Lastly, using EC-specific TERF2IP-knockout (TERF2IP-KO) mice, we found that the depletion of TERF2IP inhibited d-flow–induced EC senescence, apoptosis, and activation, as well as atherosclerotic plaque formation. These findings demonstrate that TERF2IP is an important molecular switch that simultaneously accelerates EC senescence, apoptosis, and activation by S205 phosphorylation.
Original languageEnglish (US)
JournalJCI Insight
Volume4
Issue number9
DOIs
StatePublished - May 2 2019

PMID: 31045573

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Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein. / Kotla, Sivareddy; Vu, Hang Thi; Ko, Kyung Ae; Wang, Yin; Imanishi, Masaki; Heo, Kyung-Sun; Fujii, Yuka; Thomas, Tamlyn N.; Gi, Young Jin; Mazhar, Hira; Paez-Mayorga, Jesus; Shin, Ji-Hyun; Tao, Yunting; Giancursio, Carolyn J.; Medina, Jan L.M.; Taunton, Jack; Lusis, Aldos J.; Cooke, John P.; Fujiwara, Keigi; Le, Nhat-Tu; Abe, Jun-ichi.

In: JCI Insight, Vol. 4, No. 9, 02.05.2019.

Research output: Contribution to journalArticle

Harvard

Kotla, S, Vu, HT, Ko, KA, Wang, Y, Imanishi, M, Heo, K-S, Fujii, Y, Thomas, TN, Gi, YJ, Mazhar, H, Paez-Mayorga, J, Shin, J-H, Tao, Y, Giancursio, CJ, Medina, JLM, Taunton, J, Lusis, AJ, Cooke, JP, Fujiwara, K, Le, N-T & Abe, J 2019, 'Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein' JCI Insight, vol. 4, no. 9. https://doi.org/10.1172/jci.insight.124867

APA

Kotla, S., Vu, H. T., Ko, K. A., Wang, Y., Imanishi, M., Heo, K-S., ... Abe, J. (2019). Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein. JCI Insight, 4(9). https://doi.org/10.1172/jci.insight.124867

Vancouver

Kotla S, Vu HT, Ko KA, Wang Y, Imanishi M, Heo K-S et al. Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein. JCI Insight. 2019 May 2;4(9). https://doi.org/10.1172/jci.insight.124867

Author

Kotla, Sivareddy ; Vu, Hang Thi ; Ko, Kyung Ae ; Wang, Yin ; Imanishi, Masaki ; Heo, Kyung-Sun ; Fujii, Yuka ; Thomas, Tamlyn N. ; Gi, Young Jin ; Mazhar, Hira ; Paez-Mayorga, Jesus ; Shin, Ji-Hyun ; Tao, Yunting ; Giancursio, Carolyn J. ; Medina, Jan L.M. ; Taunton, Jack ; Lusis, Aldos J. ; Cooke, John P. ; Fujiwara, Keigi ; Le, Nhat-Tu ; Abe, Jun-ichi. / Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein. In: JCI Insight. 2019 ; Vol. 4, No. 9.

BibTeX

@article{f9b3bd03213f406a9a5ca479352cdf89,
title = "Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein",
abstract = "The interplay among signaling events for endothelial cell (EC) senescence, apoptosis, and activation and how these pathological conditions promote atherosclerosis in the area exposed to disturbed flow (d-flow) in concert remain unclear. The aim of this study was to determine whether telomeric repeat-binding factor 2–interacting protein (TERF2IP), a member of the shelterin complex at the telomere, can regulate EC senescence, apoptosis, and activation simultaneously, and if so, by what molecular mechanisms. We found that d-flow induced p90RSK and TERF2IP interaction in a p90RSK kinase activity–dependent manner. An in vitro kinase assay revealed that p90RSK directly phosphorylated TERF2IP at the serine 205 (S205) residue, and d-flow increased TERF2IP S205 phosphorylation as well as EC senescence, apoptosis, and activation by activating p90RSK. TERF2IP phosphorylation was crucial for nuclear export of the TERF2IP-TRF2 complex, which led to EC activation by cytosolic TERF2IP-mediated NF-κB activation and also to senescence and apoptosis of ECs by depleting TRF2 from the nucleus. Lastly, using EC-specific TERF2IP-knockout (TERF2IP-KO) mice, we found that the depletion of TERF2IP inhibited d-flow–induced EC senescence, apoptosis, and activation, as well as atherosclerotic plaque formation. These findings demonstrate that TERF2IP is an important molecular switch that simultaneously accelerates EC senescence, apoptosis, and activation by S205 phosphorylation.",
author = "Sivareddy Kotla and Vu, {Hang Thi} and Ko, {Kyung Ae} and Yin Wang and Masaki Imanishi and Kyung-Sun Heo and Yuka Fujii and Thomas, {Tamlyn N.} and Gi, {Young Jin} and Hira Mazhar and Jesus Paez-Mayorga and Ji-Hyun Shin and Yunting Tao and Giancursio, {Carolyn J.} and Medina, {Jan L.M.} and Jack Taunton and Lusis, {Aldos J.} and Cooke, {John P.} and Keigi Fujiwara and Nhat-Tu Le and Jun-ichi Abe",
year = "2019",
month = "5",
day = "2",
doi = "10.1172/jci.insight.124867",
language = "English (US)",
volume = "4",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "9",

}

RIS

TY - JOUR

T1 - Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein

AU - Kotla, Sivareddy

AU - Vu, Hang Thi

AU - Ko, Kyung Ae

AU - Wang, Yin

AU - Imanishi, Masaki

AU - Heo, Kyung-Sun

AU - Fujii, Yuka

AU - Thomas, Tamlyn N.

AU - Gi, Young Jin

AU - Mazhar, Hira

AU - Paez-Mayorga, Jesus

AU - Shin, Ji-Hyun

AU - Tao, Yunting

AU - Giancursio, Carolyn J.

AU - Medina, Jan L.M.

AU - Taunton, Jack

AU - Lusis, Aldos J.

AU - Cooke, John P.

AU - Fujiwara, Keigi

AU - Le, Nhat-Tu

AU - Abe, Jun-ichi

PY - 2019/5/2

Y1 - 2019/5/2

N2 - The interplay among signaling events for endothelial cell (EC) senescence, apoptosis, and activation and how these pathological conditions promote atherosclerosis in the area exposed to disturbed flow (d-flow) in concert remain unclear. The aim of this study was to determine whether telomeric repeat-binding factor 2–interacting protein (TERF2IP), a member of the shelterin complex at the telomere, can regulate EC senescence, apoptosis, and activation simultaneously, and if so, by what molecular mechanisms. We found that d-flow induced p90RSK and TERF2IP interaction in a p90RSK kinase activity–dependent manner. An in vitro kinase assay revealed that p90RSK directly phosphorylated TERF2IP at the serine 205 (S205) residue, and d-flow increased TERF2IP S205 phosphorylation as well as EC senescence, apoptosis, and activation by activating p90RSK. TERF2IP phosphorylation was crucial for nuclear export of the TERF2IP-TRF2 complex, which led to EC activation by cytosolic TERF2IP-mediated NF-κB activation and also to senescence and apoptosis of ECs by depleting TRF2 from the nucleus. Lastly, using EC-specific TERF2IP-knockout (TERF2IP-KO) mice, we found that the depletion of TERF2IP inhibited d-flow–induced EC senescence, apoptosis, and activation, as well as atherosclerotic plaque formation. These findings demonstrate that TERF2IP is an important molecular switch that simultaneously accelerates EC senescence, apoptosis, and activation by S205 phosphorylation.

AB - The interplay among signaling events for endothelial cell (EC) senescence, apoptosis, and activation and how these pathological conditions promote atherosclerosis in the area exposed to disturbed flow (d-flow) in concert remain unclear. The aim of this study was to determine whether telomeric repeat-binding factor 2–interacting protein (TERF2IP), a member of the shelterin complex at the telomere, can regulate EC senescence, apoptosis, and activation simultaneously, and if so, by what molecular mechanisms. We found that d-flow induced p90RSK and TERF2IP interaction in a p90RSK kinase activity–dependent manner. An in vitro kinase assay revealed that p90RSK directly phosphorylated TERF2IP at the serine 205 (S205) residue, and d-flow increased TERF2IP S205 phosphorylation as well as EC senescence, apoptosis, and activation by activating p90RSK. TERF2IP phosphorylation was crucial for nuclear export of the TERF2IP-TRF2 complex, which led to EC activation by cytosolic TERF2IP-mediated NF-κB activation and also to senescence and apoptosis of ECs by depleting TRF2 from the nucleus. Lastly, using EC-specific TERF2IP-knockout (TERF2IP-KO) mice, we found that the depletion of TERF2IP inhibited d-flow–induced EC senescence, apoptosis, and activation, as well as atherosclerotic plaque formation. These findings demonstrate that TERF2IP is an important molecular switch that simultaneously accelerates EC senescence, apoptosis, and activation by S205 phosphorylation.

U2 - 10.1172/jci.insight.124867

DO - 10.1172/jci.insight.124867

M3 - Article

VL - 4

JO - JCI Insight

T2 - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 9

ER -

ID: 48124362