Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity.
Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity.
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DOI：
10.1021/acscentsci.7b00224
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发表时间：
2017-11-22
影响因子：
18.2
通讯作者：
Bertozzi CR
中科院分区：
文献类型：
--
作者：
Tomlin FM;Gerling-Driessen UIM;Liu YC;Flynn RA;Vangala JR;Lentz CS;Clauder-Muenster S;Jakob P;Mueller WF;Ordoñez-Rueda D;Paulsen M;Matsui N;Foley D;Rafalko A;Suzuki T;Bogyo M;Steinmetz LM;Radhakrishnan SK;Bertozzi CR
蛋白酶体抑制剂用于治疗血癌，如多发性骨髓瘤（MM）和套细胞淋巴瘤。这些药物的疗效经常被获得性耐药性破坏。蛋白酶体抑制剂抗性的一种机制可能涉及转录因子核因子红细胞2样1（NFE 2L 1，也称为Nrf 1），其通过上调蛋白酶体亚基基因表达对蛋白酶体不足或药理学抑制作出响应。这种“反弹”反应是通过一种独特的机制实现的。Nrf 1组成型易位到ER腔，N-糖基化，然后通过ER相关降解（ERAD）途径靶向蛋白酶体降解。蛋白酶体抑制导致细胞溶质Nrf 1的积累，然后将其加工形成活性转录因子。在这里，我们表明，胞质酶N-聚糖酶1（NGLY 1，人PNGase）是必不可少的Nrf 1激活蛋白酶体抑制反应。NGLY 1活性的化学或遗传破坏会导致大量被排除在细胞核之外的错误加工的Nrf 1的积累。在这些条件下，Nrf 1在调节蛋白酶体亚基基因表达以响应蛋白酶体抑制方面是无活性的。通过小分子筛选，我们确定了一种细胞活性NGLY 1抑制剂，可破坏Nrf 1的加工和功能。该化合物可增强卡非佐米（一种临床使用的蛋白酶体抑制剂）对MM和T细胞源性急性淋巴细胞白血病（T-ALL）细胞系的细胞毒性。因此，NGLY 1抑制可防止Nrf 1活化，并代表了依赖于蛋白酶体稳态的癌症的新治疗方法。胞质N-聚糖酶NGLY 1是激活转录因子Nrf 1和蛋白酶体反弹途径所必需的。蛋白酶体抑制剂细胞毒性在NGLY 1抑制后增加。
Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This “bounce-back” response is achieved through a unique mechanism. Nrf1 is constitutively translocated into the ER lumen, N-glycosylated, and then targeted for proteasomal degradation via the ER-associated degradation (ERAD) pathway. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. Here we show that the cytosolic enzyme N-glycanase 1 (NGLY1, the human PNGase) is essential for Nrf1 activation in response to proteasome inhibition. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. Under these conditions, Nrf1 is inactive in regulating proteasome subunit gene expression in response to proteasome inhibition. Through a small molecule screen, we identified a cell-active NGLY1 inhibitor that disrupts the processing and function of Nrf1. The compound potentiates the cytotoxicity of carfilzomib, a clinically used proteasome inhibitor, against MM and T cell-derived acute lymphoblastic leukemia (T-ALL) cell lines. Thus, NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis. The cytosolic N-glycanase NGLY1 is required for activation of the transcription factor Nrf1 and the proteasome bounce-back pathway. Proteasome inhibitor cytotoxicity increases upon NGLY1 inhibition.
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影响因子：
4.8
作者：
Garcia-Calvo, M;Peterson, EP;Thornberry, NA
通讯作者：
Thornberry, NA
影响因子：
4.6
作者：
Chowdhury AMMA;Katoh H;Hatanaka A;Iwanari H;Nakamura N;Hamakubo T;Natsume T;Waku T;Kobayashi A
通讯作者：
Kobayashi A
影响因子：
--
作者：
Bogyo, M;Verhelst, S;Greenbaum, D
通讯作者：
Greenbaum, D
影响因子：
--
作者：
Greenbaum, D;Medzihradszky, KF;Bogyo, M
通讯作者：
Bogyo, M
影响因子：
56.9
作者：
Greenbaum, DC;Baruch, A;Bogyo, M
通讯作者：
Bogyo, M