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

Sun Ah Jeong, Kuglae Kim, Ji Hoon Lee, Jeong Seok Cha, Prabhat Khadka, Hyun Soo Cho, In Kwon Chung

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 Aktmediated 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.

Original languageEnglish
Pages (from-to)2287-2301
Number of pages15
JournalJournal of cell science
Volume128
Issue number12
DOIs
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Cell Biology

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