Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival.
Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival.
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DOI：
10.1182/bloodadvances.2020003820
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发表时间：
2022-01-25
期刊：
影响因子：
7.5
通讯作者：
Bianchi G
中科院分区：
文献类型：
--
作者：
Chen T;Ho M;Briere J;Moscvin M;Czarnecki PG;Anderson KC;Blackwell TK;Bianchi G
MM细胞遭受蛋白质毒性并且依赖于NRF 1（蛋白酶体应激反应的主要调节剂）存活。NRF 1或其活化蛋白酶DDI 2的KO在骨髓瘤中具有细胞毒性，并克服了从头和获得性PI耐药性。多发性骨髓瘤（MM）细胞遭受基线蛋白毒性，这是由于等待蛋白水解的错误折叠蛋白质的负荷与泛素-蛋白酶体系统降解它们的能力之间的不平衡。这种内在的脆弱性是MM对干扰蛋白质稳态的药物敏感的基础，例如蛋白酶体抑制剂（PI），现代骨髓瘤治疗的支柱。原发性和获得性PI耐药是重要的临床局限性，对预后产生不利影响。PI耐药的分子机制仅部分了解，限制了药物的发展，可以克服it. The转录因子NRF 1被激活的天冬氨酸蛋白酶DNA损伤诱导1同源物2（DDI 2）后，蛋白酶体不足和管理蛋白酶体生物合成。在这篇文章中，我们表明，MM细胞表现出基线NRF 1激活，并依赖于DDI 2的生存。DDI 2敲除（KO）在体外和体内对MM细胞都具有细胞毒性。蛋白质结构-功能研究表明，DDI 2 KO阻断NRF 1裂解和核转位，导致不可逆蛋白酶体抑制后蛋白酶体活性恢复受损，从而增加对PI的敏感性。野生型而非催化死亡的DDI 2的加回完全挽救了这些表型。我们认为，DDI 2通过扰乱蛋白酶体应激反应并加剧蛋白毒性，是MM中一个尚未开发的有前途的分子靶点。
MM cells suffer from proteotoxicity and depend on NRF1, the master regulator of proteasome stress response, for survival. KO of NRF1 or its activating protease DDI2 is cytotoxic in myeloma and overcomes de novo and acquired PI resistance. Multiple myeloma (MM) cells suffer from baseline proteotoxicity as the result of an imbalance between the load of misfolded proteins awaiting proteolysis and the capacity of the ubiquitin-proteasome system to degrade them. This intrinsic vulnerability is at the base of MM sensitivity to agents that perturb proteostasis, such as proteasome inhibitors (PIs), the mainstay of modern-day myeloma therapy. De novo and acquired PI resistance are important clinical limitations that adversely affect prognosis. The molecular mechanisms underpinning PI resistance are only partially understood, limiting the development of drugs that can overcome it. The transcription factor NRF1 is activated by the aspartic protease DNA damage inducible 1 homolog 2 (DDI2) upon proteasome insufficiency and governs proteasome biogenesis. In this article, we show that MM cells exhibit baseline NRF1 activation and are dependent upon DDI2 for survival. DDI2 knockout (KO) is cytotoxic for MM cells, both in vitro and in vivo. Protein structure-function studies show that DDI2 KO blocks NRF1 cleavage and nuclear translocation, causing impaired proteasome activity recovery upon irreversible proteasome inhibition and, thereby, increasing sensitivity to PIs. Add-back of wild-type, but not of catalytically dead DDI2, fully rescues these phenotypes. We propose that DDI2 is an unexplored promising molecular target in MM by disrupting the proteasome stress response and exacerbating proteotoxicity.