Chemoproteomic profiling reveals celastrol as a potential modulator of cholesterol signaling

Geng, Yiyun; Xu, Jingyuan; Li, Weichao; Li, Qing; Shen, Chenjinxin; Deng, Zhangshuang; Zhou, Yiqing

doi:10.1039/d1cc05986f

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…Peptides with significantly changed R Ligand/Control (>1.5 or <0.67, p value <0.01) were assigned as TRPs, and the TRPs pinpoint the regions where the SIL-target engagement might occur. In agreement with the rich targetome elucidated for NPs such as artemisinin, celastrol, ,, and parthenolide, 65 proteins were assigned as the potential targets of SIL (Figure C and Table S1). Subcellular location and molecular function of gene ontology (GO) analysis revealed the wide distribution and diverse functions of the assigned targetome (Figure D and Figure S2).…”

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confidence: 72%

Living Cell-Target Responsive Accessibility Profiling Reveals Silibinin Targeting ACSL4 for Combating Ferroptosis

et al. 2022

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We report a living cell-target responsive accessibility profiling (LC-TRAP) approach to identify the targetome of silibinin (SIL), a well-established hepatoprotective natural product (NP), in HepG2 cells. Proteins showing accessibility changes, probed by covalent lysine labeling reagents and leveraged by multiplexed quantitative proteomics, following the administration of SIL to the living cells were assigned as potential targets. Among the assigned targetome, ACSL4, an enzyme essential for ferroptosis induction, might be involved in the hepatoprotective effects of SIL and hence was intensively validated. We first demonstrated that SIL protected HepG2 cells from ferroptosis dependent on ACSL4. Then, we used biophysical assays and a SIL-derivatized chemical probe to corroborate that SIL can bind to ACSL4. The ensuing enzymatic assays showed that SIL inhibited ACSL4 enzymatic activity, thereby mitigating the ACSL4-mediated ferroptosis. As such, we revealed that ACSL4 inhibition, using SIL as a model compound, represents a promising hepatoprotective strategy. Further, since TRAP probes the accessibility changes of reactive proteinaceous lysines, it can pinpoint the proximal regions where the ligand engagement may occur. Thus, the LC-TRAP analysis of SIL, the newly discovered ligand of ACSL4, and arachidonic acid (AA), the substrate, intriguingly showed that SIL and AA both affected the conformation of the K536-proximal region of ACSL4, albeit through distinct binding patterns. Collectively, we describe a straightforward LC-TRAP workflow that does not involve ligand-derived probe synthesis and is widely applicable to target discovery of NPs.

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supporting

confidence: 72%

Living Cell-Target Responsive Accessibility Profiling Reveals Silibinin Targeting ACSL4 for Combating Ferroptosis

et al. 2022

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“…Given the multiple pharmacological effects of celastrol, the potential targets of celastrol had been discovered using recombinant proteins or proteasomes derived from cell lysate: STAT3 for cardiac remodeling; Hsp90, proteasome, Prdx1/2, , Cdc37, GSTO1, PDI, Annexin II, eEF1A, and β-tubulin for tumor; FASN, LSS, DHCR7, and DHCR24 for lipid metabolism; p23 for steroid receptor-dependent disease; and HMGB1, IKKβ, and Nur77 for inflammation. These identified possible targets were not directly related to the mechanism of celastrol against fibroblast–myofibroblast transformation (FMT), which is the core event in PF, thus its direct targets in pulmonary fibroblasts are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast–Myofibroblast Transformation against Pulmonary Fibrosis

Zhang

Shen

et al. 2022

ACS Chem. Biol.

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Celastrol (CEL), a pentacyclic triterpene compound, has been proven to have a definite antipulmonary fibrosis effect. However, its direct targets for antipulmonary fibrosis remain unknown. In this study, we designed and synthesized a series of celastrol-based probes to identify the direct targets in human pulmonary fibroblasts using an activity-based protein profiling strategy. Among many fished targets, we identified a key protein, cullin-associated and neddylation-dissociated 1 (CAND1), which was involved in fibroblast–myofibroblast transformation (FMT). More importantly, we found that the inhibitory effect of celastrol on FMT is dependent on CAND1, through improving the interactions between CAND1 and Cullin1 to promote the activity of Skp1/Cullin1/F-box ubiquitin ligases. In silico studies and cysteine mutation experiments further demonstrated that Cys264 of CAND1 is the site for conjugation of celastrol. This reveals a new mechanism of celastrol against pulmonary fibrosis and may provide a novel therapeutic option for antipulmonary fibrosis.

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Celastrol functions as an emerging manager of lipid metabolism: Mechanism and therapeutic potential

Shi

Zhu

et al. 2023

Biomedicine & Pharmacotherapy

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Chemoproteomic profiling reveals celastrol as a potential modulator of cholesterol signaling

Abstract: We report a quantitative chemoproteomic approach that utilizes a clickable photoreactive probe for global profiling of celastrol targets, which may significantly improve the current understanding of celastrol’s mode of action.

Cited by 4 publications

References 26 publications

Living Cell-Target Responsive Accessibility Profiling Reveals Silibinin Targeting ACSL4 for Combating Ferroptosis

Living Cell-Target Responsive Accessibility Profiling Reveals Silibinin Targeting ACSL4 for Combating Ferroptosis

Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast–Myofibroblast Transformation against Pulmonary Fibrosis

Celastrol functions as an emerging manager of lipid metabolism: Mechanism and therapeutic potential

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