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Novel activity of KRAB domain that functions to reinforce nuclear localization of KRAB-containing zinc finger proteins by interacting with KAP1

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Abstract

Previously, we found that two isoforms of the ZNF268 gene (ZNF268a and ZNF268b2, with and without the KRAB domain, respectively) might play distinct roles in normal epithelia and in cervical cancer. Here we further investigated that KRAB domain defined the function disparity in part by reinforcing nuclear localization of ZNF268a. We found that the A-box of KRAB alone retained major specific nuclear localization activity. In contrast, the B-box alone did not have nuclear localization activity but enhanced it significantly. Consistent with the critical function of the A-box, each mutation of six conserved residues (V9, V11, F13, E16, E17 and W18) in the A-box dramatically impaired nuclear localization activity. Furthermore, the unique nuclear localization activity of KRAB was verified in seven additional KRAB-containing zinc finger proteins (KRAB-ZFPs), suggesting that it is a universal feature of KRAB-ZFPs. Finally, KRAB exerted its unique nuclear localization activity by interacting with the RBCC domain of its corepressor KAP1. Our results have revealed a novel mechanism by which the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. Our study also suggests that loss of the KRAB domain in KRAB-ZFPs due to aberrant alternative splicing might contribute to carcinogenesis.

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Acknowledgments

This work was supported by a National High Technology Research and Development Program of China (863 Program; grant no. 2006AA02A306 to W. Li), National Natural Science Foundation of China (grant nos. 30871245 and 31271511 to M. Guo, 81070406 to Z. Huang), and a Ph.D. Programs Foundation of Ministry of Education of China (grant no. 20110141110016 to Z. Huang), New Century Excellent Talents in University (NCET) of Ministry of Education of China (grant no. NCET-12-0422 to Z. Huang), Scientific Research Foundation for Returned Scholars of Ministry of Education of China (to Z. Huang).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People’s Republic of China

    Wei Wang, Jinyang Cai, Yingliang Wu, Li Hu, Zongyun Chen, Jun Hu, Wenxin Li & Mingxiong Guo

  2. Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People’s Republic of China

    Zan Huang

  3. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China

    Ze Chen

Authors
  1. Wei Wang
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  2. Jinyang Cai
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  3. Yingliang Wu
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  4. Li Hu
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  5. Zongyun Chen
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  6. Jun Hu
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  7. Ze Chen
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  8. Wenxin Li
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  9. Mingxiong Guo
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  10. Zan Huang
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Corresponding authors

Correspondence to Mingxiong Guo or Zan Huang.

Additional information

W. Wang and J. Cai contributed equally to this work.

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Wang, W., Cai, J., Wu, Y. et al. Novel activity of KRAB domain that functions to reinforce nuclear localization of KRAB-containing zinc finger proteins by interacting with KAP1. Cell. Mol. Life Sci. 70, 3947–3958 (2013). https://doi.org/10.1007/s00018-013-1359-4

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  • DOI: https://doi.org/10.1007/s00018-013-1359-4

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