Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11

Li, Jing; Zhang, Yaru; Santos, Bruno Da Silva Sil Dos; Wang, Rui; Ma, Yuyong; Perez, Christian; Yang, Yi-Yan; Peng, Junmin; Cohen, Seth M.; Chou, Tsui‐Fen; Hilton, Stephen T.; Deshaies, Raymond J.

doi:10.1016/j.chembiol.2018.07.012

Cited by 32 publications

(28 citation statements)

References 41 publications

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“…One core component of the lid is a Jab1/MPN domain-associated metalloisopeptidase (JAMM) domain-containing protein Rpn11 (POH1/PSMD14) that couples deubiquitination with degradation ( Figure 1B) [35,36]. The development of Rpn11 inhibitors might have the ability to expand effective UPS inhibitors in the clinic, as discussed below [37][38][39][40]. The base of the 19S RP includes a ring-shaped heterohexamer of AAA+ ATPases that engage and unfold substrate polypeptides to allow for their translocation into the proteolytic pore of the 20S CP [8,16,31].…”

Section: S Proteasomementioning

confidence: 99%

“…In addition to capzimin, natural products such as thiolutin and gliotoxin were also identified as active inhibitors of JAMM proteases, including Rpn11. These compounds are active in cell culture and inhibit proteasome function by chelating the zinc ion in the Rpn11 active site [38,39]. However, these compounds are less specific towards Rpn11 than capzimin.…”

Section: Block the Removal Of Ubiquitin Chains From Substrates: Rpn11mentioning

confidence: 99%

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Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

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Section: S Proteasomementioning

confidence: 99%

Section: Block the Removal Of Ubiquitin Chains From Substrates: Rpn11mentioning

confidence: 99%

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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“…Previous studies have demonstrated that PSMD14 promotes tumor progression by regulating key anti-cancer proteins such as c-jun, p53, SNAIL, mTOR, and E2F1 [17][18][19][20][21][22]24]. Importantly, small molecule inhibitors targeting PSMD14 were shown to be prospects for potential clinical application [25][26][27][28]. However, the expression of PSMD14 in NSCLC and the underlying mechanism by which PSMD14 is involved in NSCLC development remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of deubiquitinase PSMD14 in lung adenocarcinoma (LUAD) and its prognostic significance

Zhang¹,

Xu²,

Ma³

et al. 2020

J. Cancer

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PSMD14 is a 19S-proteasome-associated deubiquitinating enzyme that facilitates protein degradation by the 20S proteasome core particle. Although accumulating evidence indicates that PSMD14 has emerged as a critical oncogenic factor by promoting tumor growth, the expression and function of PSMD14 in non-small cell lung cancer (NSCLC) remain largely unknown. In this study, we assessed PSMD14 expression and correlated it with clinical-pathological features and patient survival in NSCLC. We also determined the roles of PSMD14 in the regulation of lung adenocarcinoma (LUAD) cell growth. The results showed that PSMD14 expression was significantly upregulated in human NSCLC tissues compared with adjacent non-cancerous tissues. The PSMD14 level was associated with tumor size, lymph node invasion, and TNM stage in LUAD patients. Importantly, high PSMD14 expression was associated with poor overall survival (OS) and disease-free survival (DFS) in LUAD patients. Further, knockdown of PSMD14 significantly inhibited cell growth and caused G1 arrest and cellular senescence by increasing p21 stability in LUAD cells. PSMD14 knockdown also promoted cell apoptosis by increasing cleaved caspase-3 levels in H1299 cells. PSMD14 may serve as a potential prognostic marker and therapeutic target for LUAD patients.

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“…Further evidence revealed that necrotic cell death induced by GT in murine thymocytes is associated with activation of a redox active calcium channel in the plasma membrane (Hurne et al, 2002). The inhibition of proteasome activity is one of the putative molecular targets of GT-mediated apoptosis in immune cells (Kroll et al, 1999;Dolan et al, 2015;Li et al, 2018). Based on the fact that the disulfide bridge of GT allows the cross linking with proteins and generates reactive oxygen species (ROS) through the redox cycling between reduced and oxidized forms, ROS is believed to be also responsible for DNA damage and apoptosis in cells of immune system (Harms et al, 2015;Nouri et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Novel Action Targets of Natural Product Gliotoxin in Photosynthetic Apparatus

Guo

Cheng

et al. 2020

Front. Plant Sci.

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Gliotoxin (GT) is a fungal secondary metabolite that has attracted great interest due to its high biological activity since it was discovered by the 1930s. It exhibits a unique structure that contains a N-C = O group as the characteristics of the classical PSII inhibitor. However, GT's phytotoxicity, herbicidal activity and primary action targets in plants remain hidden. Here, it is found that GT can cause brown or white leaf spot of various monocotyledonous and dicotyledonous plants, being regarded as a potential herbicidal agent. The multiple sites of GT action are located in two photosystems. GT decreases the rate of oxygen evolution of PSII with an I 50 value of 60 µM. Chlorophyll fluorescence data from Chlamydomonas reinhardtii cells and spinach thylakoids implicate that GT affects both PSII electron transport at the acceptor side and the reduction rate of PSI end electron acceptors' pool. The major direct action target of GT is the plastoquinone Q B-site of the D1 protein in PSII, where GT inserts in the Q B binding niche by replacing native plastoquinone (PQ) and then interrupts electron flow beyond plastoquinone Q A. This leads to severe inactivation of PSII RCs and a significant decrease of PSII overall photosynthetic activity. Based on the simulated modeling of GT docking to the D1 protein of spinach, it is proposed that GT binds to the-Q B-site through two hydrogen bonds between GT and D1-Ser264 and D1-His252. A hydrogen bond is formed between the aromatic hydroxyl oxygen of GT and the residue Ser264 in the D1 protein. The 4-carbonyl group of GT provides another hydrogen bond to the residue D1-His252. So, it is concluded that GT is a novel natural PSII inhibitor. In the future, GT may have the potential for development into a bioherbicide or being utilized as a lead compound to design more new derivatives.

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Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11

Cited by 32 publications

References 41 publications

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Upregulation of deubiquitinase PSMD14 in lung adenocarcinoma (LUAD) and its prognostic significance

Novel Action Targets of Natural Product Gliotoxin in Photosynthetic Apparatus

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