HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells.
Wen-Fang WangLi YanZhao LiuLan-Xuan LiuJian LinZhi-Yin LiuXiong-Ping ChenWu ZhangZi-Zhen XuTing ShiJun-Min LiYi-Lei ZhaoGuoyu MengYi XiaJian-Yong LiJiang ZhuPublished in: Nature communications (2017)
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.
Keyphrases
- heat shock protein
- diffuse large b cell lymphoma
- heat shock
- wild type
- epstein barr virus
- heat stress
- transcription factor
- gene expression
- dna methylation
- genome wide
- protein protein
- binding protein
- cell proliferation
- single cell
- mesenchymal stem cells
- signaling pathway
- bone marrow
- diabetic rats
- pi k akt
- stress induced