HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells

Wen-Fang Wang, Li Yan, Zhao Liu, Lan-Xuan Liu, Jian Lin, Zhi-Yin Liu, Xiong-Ping Chen, Wu Zhang, Zi-Zhen Xu, Ting Shi, Jun-Min Li, Yi-Lei Zhao, Guoyu Meng, Yi Xia, Jian-Yong Li and Jiang Zhu ()
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Wen-Fang Wang: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Li Yan: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Zhao Liu: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Lan-Xuan Liu: Shanghai Jiao Tong University
Jian Lin: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Zhi-Yin Liu: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Xiong-Ping Chen: Shanghai Jiao Tong University
Wu Zhang: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Zi-Zhen Xu: Shanghai Jiao Tong University
Ting Shi: Shanghai Jiao Tong University
Jun-Min Li: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yi-Lei Zhao: Shanghai Jiao Tong University
Guoyu Meng: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yi Xia: The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital
Jian-Yong Li: The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital
Jiang Zhu: Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract B lymphocyte-induced maturation protein-1 (Blimp-1) ensures B-cell differentiation into the plasma cell stage, and its instability constitutes a crucial oncogenic element in certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). However, the underlying degradation mechanisms and their possible therapeutic relevance remain unexplored. Here, we show that N-terminal misfolding mutations in ABC-DLBCL render Blimp-1 protein susceptible to proteasome-mediated degradation but spare its transcription-regulating activity. Mechanistically, whereas wild-type Blimp-1 metabolism is triggered in the nucleus through PML-mediated sumoylation, the degradation of lymphoma-associated mutants is accelerated by subversion of this pathway to Hrd1-mediated cytoplasmic sequestration and ubiquitination. Screening experiments identifies the heat shock protein 70 (HSP70) that selects Blimp-1 mutants for Hrd1 association, and HSP70 inhibition restores their nuclear accumulation and oncorepressor activities without disrupting normal B-cell maturation. Therefore, HSP70-Hrd1 axis represents a potential therapeutic target for restoring the oncorepressor activity of unstable lymphoma-associated Blimp-1 mutants.

Date: 2017
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DOI: 10.1038/s41467-017-00476-w

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