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Akt-mediated phosphorylation increases the binding affinity of hTERT for importin α to promote nuclear translocation.

Jeong SA, Kim K, Lee JH, Cha JS, Khadka P, Cho HS, Chung IK
J Cell Sci 128 2287-301 (2015)
Cited: 23 times
EuropePMC logo PMID: 25999477

Abstract

Telomeres are essential for chromosome integrity and protection, and their maintenance requires the ribonucleoprotein enzyme telomerase. Previously, we have shown that human telomerase reverse transcriptase (hTERT) contains a bipartite nuclear localization signal (NLS; residues 222-240) that is responsible for nuclear import, and that Akt-mediated phosphorylation of residue S227 is important for efficient nuclear import of hTERT. Here, we show that hTERT binds to importin-α proteins through the bipartite NLS and that this heterodimer then forms a complex with importin-β proteins to interact with the nuclear pore complex. Depletion of individual importin-α proteins results in a failure of hTERT nuclear import, and the resulting cytoplasmic hTERT is degraded by ubiquitin-dependent proteolysis. Crystallographic analysis reveals that the bipartite NLS interacts with both the major and minor sites of importin-α proteins. We also show that Akt-mediated phosphorylation of S227 increases the binding affinity for importin-α proteins and promotes nuclear import of hTERT, thereby resulting in increased telomerase activity. These data provide details of a binding mechanism that enables hTERT to interact with the nuclear import receptors and of the control of the dynamic nuclear transport of hTERT through phosphorylation.

Reviews - 4b18 mentioned but not cited (2)

  1. Diversification of importin-α isoforms in cellular trafficking and disease states. Pumroy RA, Cingolani G. Biochem J 466 13-28 (2015)
  2. How Influenza Virus Uses Host Cell Pathways during Uncoating. Moreira EA, Yamauchi Y, Matthias P. Cells 10 1722 (2021)

Articles - 4b18 mentioned but not cited (2)

  1. Structural basis for nuclear import selectivity of pioneer transcription factor SOX2. Jagga B, Edwards M, Pagin M, Wagstaff KM, Aragão D, Roman N, Nanson JD, Raidal SR, Dominado N, Stewart M, Jans DA, Hime GR, Nicolis SK, Basler CF, Forwood JK. Nat Commun 12 28 (2021)
  2. Structural characterization of human importin alpha 7 in its cargo-free form at 2.5 Å resolution. Tsimbalyuk S, Donnelly CM, Forwood JK. Sci Rep 12 315 (2022)


Reviews citing this publication (8)

  1. Structural Biology and Regulation of Protein Import into the Nucleus. Christie M, Chang CW, Róna G, Smith KM, Stewart AG, Takeda AA, Fontes MR, Stewart M, Vértessy BG, Forwood JK, Kobe B. J Mol Biol 428 2060-2090 (2016)
  2. Towards an understanding of regulating Cajal body activity by protein modification. Hebert MD, Poole AR. RNA Biol 14 761-778 (2017)
  3. Telomeres in Plants and Humans: Not So Different, Not So Similar. Procházková Schrumpfová P, Fojtová M, Fajkus J. Cells 8 E58 (2019)
  4. Composition and Function of Telomerase-A Polymerase Associated with the Origin of Eukaryotes. Schrumpfová PP, Fajkus J. Biomolecules 10 E1425 (2020)
  5. Alternative Splicing of Human Telomerase Reverse Transcriptase (hTERT) and Its Implications in Physiological and Pathological Processes. Plyasova AA, Zhdanov DD. Biomedicines 9 526 (2021)
  6. Nuclear-Import Receptors Counter Deleterious Phase Transitions in Neurodegenerative Disease. Odeh HM, Fare CM, Shorter J. J Mol Biol 434 167220 (2022)
  7. The nuclear transportation of PD-L1 and the function in tumor immunity and progression. Qu L, Jin J, Lou J, Qian C, Lin J, Xu A, Liu B, Zhang M, Tao H, Yu W. Cancer Immunol Immunother 71 2313-2323 (2022)
  8. Post-Transcriptional and Post-Translational Modifications in Telomerase Biogenesis and Recruitment to Telomeres. Shepelev N, Dontsova O, Rubtsova M. Int J Mol Sci 24 5027 (2023)

Articles citing this publication (11)

  1. Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation. Beyer AM, Freed JK, Durand MJ, Riedel M, Ait-Aissa K, Green P, Hockenberry JC, Morgan RG, Donato AJ, Peleg R, Gasparri M, Rokkas CK, Santos JH, Priel E, Gutterman DD. Circ Res 118 856-866 (2016)
  2. A novel cell-penetrating peptide protects against neuron apoptosis after cerebral ischemia by inhibiting the nuclear translocation of annexin A1. Li X, Zheng L, Xia Q, Liu L, Mao M, Zhou H, Zhao Y, Shi J. Cell Death Differ 26 260-275 (2019)
  3. Telomere length and reactive oxygen species levels are positively associated with a high risk of mortality and recurrence in hepatocellular carcinoma. Ko E, Seo HW, Jung G. Hepatology 67 1378-1391 (2018)
  4. Fucoidan Induces ROS-Dependent Apoptosis in 5637 Human Bladder Cancer Cells by Downregulating Telomerase Activity via Inactivation of the PI3K/Akt Signaling Pathway. Han MH, Lee DS, Jeong JW, Hong SH, Choi IW, Cha HJ, Kim S, Kim HS, Park C, Kim GY, Moon SK, Kim WJ, Hyun Choi Y. Drug Dev Res 78 37-48 (2017)
  5. Shorter telomeres and high telomerase activity correlate with a highly aggressive phenotype in breast cancer cell lines. Ceja-Rangel HA, Sánchez-Suárez P, Castellanos-Juárez E, Peñaroja-Flores R, Arenas-Aranda DJ, Gariglio P, Benítez-Bribiesca L. Tumour Biol 37 11917-11926 (2016)
  6. Intrinsically Disordered Linkers Impart Processivity on Enzymes by Spatial Confinement of Binding Domains. Szabo B, Horvath T, Schad E, Murvai N, Tantos A, Kalmar L, Chemes LB, Han KH, Tompa P. Int J Mol Sci 20 E2119 (2019)
  7. Nuclear localisation of 53BP1 is regulated by phosphorylation of the nuclear localisation signal. von Morgen P, Lidak T, Horejsi Z, Macurek L. Biol Cell 110 137-146 (2018)
  8. Structural and mechanistic insights into nuclear transport and delivery of the critical pluripotency factor Oct4 to DNA. Okuyama T, Yamagishi R, Shimada J, Ikeda M, Maruoka Y, Kaneko H. J Biomol Struct Dyn 36 767-778 (2018)
  9. Telomere Maintenance Pathway Activity Analysis Enables Tissue- and Gene-Level Inferences. Nersisyan L, Simonyan A, Binder H, Arakelyan A. Front Genet 12 662464 (2021)
  10. Establishment of an Efficient Immortalization Strategy Using HMEJ-Based bTERT Insertion for Bovine Cells. Zhang Z, Han Z, Guo Y, Liu X, Gao Y, Zhang Y. Int J Mol Sci 22 12540 (2021)
  11. Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease. Ait-Aissa K, Norwood-Toro LE, Terwoord J, Young M, Paniagua LA, Hader SN, Hughes WE, Hockenberry JC, Beare JE, Linn J, Kohmoto T, Kim J, Betts DH, LeBlanc AJ, Gutterman DD, Beyer AM. Function (Oxf) 3 zqac043 (2022)


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