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Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3

Oncogene volume 24, pages 5401–5413 (2005)Cite this article

Abstract

The PML gene of acute promyelocytic leukemia (APL) encodes a cell-growth and tumor suppressor. PML localizes to discrete nuclear bodies (NBs) that are disrupted in APL cells, resulting from a reciprocal chromosome translocation t (15;17). Here we show that the nuclear localization of PML is also regulated by SUMO-3, one of the three recently identified SUMO isoforms in human cells. SUMO-3 bears similar subcellular distribution to those of SUMO-1 and -2 in the interphase nuclear body, which is colocalized with PML protein. However, both SUMO-2 and -3 are also localized to nucleoli, a region lacking SUMO-1. Immunoprecipitated PML protein bears SUMO-3 moiety in a covalently modified form, supporting the notion that PML is conjugated by SUMO-3. To determine the functional relevance of SUMO-3 conjugation on PML molecular dynamics, we suppressed SUMO-3 protein expression using a siRNA-mediated approach. Depletion of SUMO-3 markedly reduced the number of PML-containing NBa and their integrity, which is rescued by exogenous expression of SUMO-3 but not SUMO-1 or SUMO-2. The specific requirement of SUMO-3 for PML nuclear localization is validated by expression of SUMO-3 conjugation defective mutant. Moreover, we demonstrate that oligomerization of SUMO-3 is required for PML retention in the nucleus. Taken together, our studies provide first line of evidence showing that SUMO-3 is essential for PML localization and offer novel insight into the pathobiochemistry of APL.

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Acknowledgements

We thank Drs Gordon Leitch and Shyam Reddy for critical reviews of this manuscript and members of our groups for insightful discussion during the course of this study. This work was supported by grants from Chinese Natural Science Foundation (39925018 and 30121001), Chinese Academy of Science (KSCX2-2-01), Chinese 973 project (2002CB713700), American Cancer Society (RPG-99-173-01) and National Institutes of Health (CA89019; DK56292) to XY. XY is GCC Distinguished Cancer Research Scholar.

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  1. Chuanhai Fu and Kashif Ahmed: These two authors contributed equally to this work

Authors and Affiliations

  1. School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China

    Chuanhai Fu, Kashif Ahmed, Husheng Ding, Yong Miao, Yunyu Shi, Jingde Zhu & Xuebiao Yao

  2. Department of Physiology, Morehouse School of Medicine, Atlanta, 30310, GA, USA

    Chuanhai Fu, Xia Ding & Xuebiao Yao

  3. Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hongzhou, 310003, China

    Jianping Lan, Yuanyuan Zhu & He Huang

  4. Proteomics Research Laboratory, Beijing, 100086, China

    Zhihong Yang

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  1. Chuanhai Fu
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Correspondence to He Huang or Xuebiao Yao.

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Fu, C., Ahmed, K., Ding, H. et al. Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3. Oncogene 24, 5401–5413 (2005). https://doi.org/10.1038/sj.onc.1208714

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