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

Sivareddy Kotla, Nhat Tu Le, Hang Thi Vu, Kyung Ae Ko, Young Jin Gi, Tamlyn N. Thomas, Carolyn Giancursio, Aldos J. Lusis, John P. Cooke, Keigi Fujiwara, Jun ichi Abe

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number153962
JournalMetabolism: clinical and experimental
Volume100
DOIs
StatePublished - Nov 2019

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Telomeric Repeat Binding Protein 2
Ubiquitin-Protein Ligases
Phenotype
Endothelial Cells
Phosphorylation
Cell Aging
Telomere
Sirolimus
Atherosclerosis
Apoptosis
Telomere Shortening
Gene Expression
Cell Nucleus Active Transport
Telomerase
Gene Expression Profiling
Principal Component Analysis
Genes

Keywords

  • Inflammation
  • MKRN1
  • Senescence
  • Senescence-associated secretory phenotype (SASP)
  • Telomeric repeat binding factor 2-interacting protein (TERF2IP)
  • p90RSK

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase. / Kotla, Sivareddy; Le, Nhat Tu; Vu, Hang Thi; Ko, Kyung Ae; Gi, Young Jin; Thomas, Tamlyn N.; Giancursio, Carolyn; Lusis, Aldos J.; Cooke, John P.; Fujiwara, Keigi; Abe, Jun ichi.

In: Metabolism: clinical and experimental, Vol. 100, 153962, 11.2019.

Research output: Contribution to journalArticle

Kotla, Sivareddy ; Le, Nhat Tu ; Vu, Hang Thi ; Ko, Kyung Ae ; Gi, Young Jin ; Thomas, Tamlyn N. ; Giancursio, Carolyn ; Lusis, Aldos J. ; Cooke, John P. ; Fujiwara, Keigi ; Abe, Jun ichi. / Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase. In: Metabolism: clinical and experimental. 2019 ; Vol. 100.
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abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: 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.",
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author = "Sivareddy Kotla and Le, {Nhat Tu} and Vu, {Hang Thi} and Ko, {Kyung Ae} and Gi, {Young Jin} and Thomas, {Tamlyn N.} and Carolyn Giancursio and Lusis, {Aldos J.} and Cooke, {John P.} and Keigi Fujiwara and Abe, {Jun ichi}",
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T1 - Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase

AU - Kotla, Sivareddy

AU - Le, Nhat Tu

AU - Vu, Hang Thi

AU - Ko, Kyung Ae

AU - Gi, Young Jin

AU - Thomas, Tamlyn N.

AU - Giancursio, Carolyn

AU - Lusis, Aldos J.

AU - Cooke, John P.

AU - Fujiwara, Keigi

AU - Abe, Jun ichi

PY - 2019/11

Y1 - 2019/11

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

KW - Inflammation

KW - MKRN1

KW - Senescence

KW - Senescence-associated secretory phenotype (SASP)

KW - Telomeric repeat binding factor 2-interacting protein (TERF2IP)

KW - p90RSK

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