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Nat Commun. 2017 Aug 25;8(1):363. doi: 10.1038/s41467-017-00476-w.

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

Author information

1
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
2
State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
3
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
4
Department of Laboratory Medicine, Rui-Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People's Republic of China.
5
The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, People's Republic of China.
6
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China. zhujiang@shsmu.edu.cn.

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.The transcriptional repressor Blimp-1 has an important role in B-cell differentiation. Here the authors show that lymphoma-associated Blimp-1 mutants are selectively recognized by HSP70-Hrd1, which leads to their accelerated degradation and propose HSP70 inhibition as a therapeutic approach for certain lymphomas.

PMID:
28842558
PMCID:
PMC5572455
DOI:
10.1038/s41467-017-00476-w
[Indexed for MEDLINE]
Free PMC Article

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