A stress response p38 MAP kinase inhibitor SB202190 promoted TFEB/TFE3-dependent autophagy and lysosomal biogenesis independent of p38

Yang, Chuanbin; Zhu, Zhou; Tong, Benjamin Chun‐Kit; Iyaswamy, Ashok; Xie, Wen-Jian; Zhu, Yuechun; Sreenivasmurthy, Sravan Gopalkrishnashetty; Krishnamoorthi, Senthilkumar; Cheung, King‐Ho; Song, Ju‐Xian; Zhang, Hongjie; Li, Min

doi:10.1016/j.redox.2020.101445

Cited by 45 publications

(43 citation statements)

References 67 publications

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“…When assessing the abundance of acidic compartments, significant increases were only observed for Enza, GF and SB90, whereas no treatment led to identifiable activation of TFEB driven lysosomal biogenesis. This is contrary to other reports which indicate there is TFEB translocation upon treatment with SB90, corresponding to classical TFEB activation and lysosomal biogenesis (Yang et al, 2020).…”

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confidence: 99%

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

Svanbergsson

Martinsson

et al. 2021

Preprint

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Aggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the induced pathologys traits similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic intervention. High-throughput screening (HTS) of annotated compound libraries could facilitate mechanistic investigation by identifying targets with impact on α-synuclein aggregation. To this end, we developed a FRET-based cellular reporter in HEK293T cells, with sensitivity down to 6.5 nM α-synuclein seeds. Using this model system, we identified GF109203X, SB202190, and SB203580 as inhibitors capable of preventing induction of α-synuclein aggregation via inhibition of p38 MAPK and PKC, respectively. Our findings highlight the value HTS brings to the mechanistic investigation of α-synuclein aggregation while simultaneously identifying novel therapeutic compounds.

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confidence: 99%

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

Svanbergsson

Martinsson

et al. 2021

Preprint

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“…SB203850 has an IC 50 of 300-500 nM. Moreover, it was recently reported that SB202190 should not be used in research studies as an inhibitor of p38 MAPK due to its action on the autophagy-lysosomal axis [22]. Using a highly specific inhibitor, the current study showed that unloading-induced p38α MAP kinase phosphorylation was significantly reduced in the presence of VX-745 inhibitor.…”

Section: Discussionmentioning

confidence: 59%

P38α-MAPK Signaling Inhibition Attenuates Soleus Atrophy during Early Stages of Muscle Unloading

Belova

Mochalova

Kostrominova

et al. 2020

IJMS

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To test the hypothesis that p38α-MAPK plays a critical role in the regulation of E3 ligase expression and skeletal muscle atrophy during unloading, we used VX-745, a selective p38α inhibitor. Three groups of rats were used: non-treated control (C), 3 days of unloading/hindlimb suspension (HS), and 3 days HS with VX-745 inhibitor (HSVX; 10 mg/kg/day). Total weight of soleus muscle in HS group was reduced compared to C (72.3 ± 2.5 vs 83.0 ± 3 mg, respectively), whereas muscle weight in the HSVX group was maintained (84.2 ± 5 mg). The expression of muscle RING-finger protein-1 (MuRF1) mRNA was significantly increased in the HS group (165%), but not in the HSVX group (127%), when compared with the C group. The expression of muscle-specific E3 ubiquitin ligases muscle atrophy F-box (MAFbx) mRNA was increased in both HS and HSVX groups (294% and 271%, respectively) when compared with C group. The expression of ubiquitin mRNA was significantly higher in the HS (423%) than in the C and HSVX (200%) groups. VX-745 treatment blocked unloading-induced upregulation of calpain-1 mRNA expression (HS: 120%; HSVX: 107%). These results indicate that p38α-MAPK signaling regulates MuRF1 but not MAFbx E3 ligase expression and inhibits skeletal muscle atrophy during early stages of unloading.

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“…To our knowledge, our results are the first to report that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. Of note, recent studies found that TFE3 dephosphorylation and translocation of TFE3 into the nucleus may be triggered by increased intracellular Ca 2+ levels and PPP3/calcineurin activation 57 , 58 . Thus, it is possible that TFE3 activity may be also regulated by the Ca 2+ -PPP3/calcineurin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

et al. 2020

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Background and Aim: Increasing evidence suggests that spinal cord injury (SCI)-induced defects in autophagic flux may contribute to an impaired ability for neurological repair following injury. Transcription factor E3 (TFE3) plays a crucial role in oxidative metabolism, lysosomal homeostasis, and autophagy induction. Here, we investigated the role of TFE3 in modulating autophagy following SCI and explored its impact on neurological recovery. Methods: Histological analysis via HE, Nissl and Mason staining, survival rate analysis, and behavioral testing via BMS and footprint analysis were used to determine functional recovery after SCI. Quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, TUNEL staining, enzyme-linked immunosorbent assays, and immunoprecipitation were applied to examine levels of autophagy flux, ER-stress-induced apoptosis, oxidative stress, and AMPK related signaling pathways. In vitro studies using PC12 cells were performed to discern the relationship between ROS accumulation and autophagy flux blockade. Results: Our results showed that in SCI, defects in autophagy flux contributes to ER stress, leading to neuronal death. Furthermore, SCI enhances the production of reactive oxygen species (ROS) that induce lysosomal dysfunction to impair autophagy flux. We also showed that TFE3 levels are inversely correlated with ROS levels, and increased TFE3 levels can lead to improved outcomes. Finally, we showed that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. Conclusions: TFE3 is an important regulator in ROS-mediated autophagy dysfunction following SCI, and TFE3 may serve as a promising target for developing treatments for SCI.

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A stress response p38 MAP kinase inhibitor SB202190 promoted TFEB/TFE3-dependent autophagy and lysosomal biogenesis independent of p38

Cited by 45 publications

References 67 publications

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation

P38α-MAPK Signaling Inhibition Attenuates Soleus Atrophy during Early Stages of Muscle Unloading

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

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