Sestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1

Ro, Seung Hyun; Semple, Ian A.; Park, Haewon; Park, Haeli; Park, Hwan‐Woo; Kim, Myung-Jin; Kim, Jeong Sig; Lee, Jun Hee

doi:10.1111/febs.12905

Cited by 100 publications

(88 citation statements)

References 44 publications

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“…29 In a recent study, SESN2 was shown to also induce autophagic degradation of SQSTM1 by promoting ULK1-mediated SQSTM1 phosphorylation via its interaction with ULK1 and SQSTM1. 38 Based on these data and our result that SESN2 induces mitophagy by mediating SQSTM1 binding to ubiquitinated mitochondria via its interaction with SQSTM1, we speculate that SESN2 may be involved in SQSTM1-mediated autophagic degradation through its binding to SQSTM1 and/or SQSTM1 target proteins in response to various cellular stresses. Although we did not identify any Lys63 ubiquitinated proteins on the mitochondrial surface which interacted with SESN2 or SQSTM1, we suggest that SESN2 functions as a scaffold protein that strengthens the otherwise weak association of SQSTM1 with ubiquitinated proteins on mitochondria, resulting in mitophagy.…”

Section: Discussionsupporting

confidence: 59%

“…29,38 Several studies have revealed that signal-dependent phosphorylation of SQSTM1 at specific sites (Ser349, Ser351, Ser403) is critical to degradation of ubiquitinated proteins targeted by SQSTM1 by reinforcing interactions between them. 29,39,40 Therefore, we first examined the extent of phosphorylation of SQSTM1 at Ser349, Ser351, and Ser403 in Sesn2 C/C BMDMs in the absence or presence of stimulation.…”

Section: Sesn2 Induces Mitochondrial Priming By Facilitating Perinuclmentioning

confidence: 99%

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SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

et al. 2016

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Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces "mitochondrial priming" by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.

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Section: Discussionsupporting

confidence: 59%

Section: Sesn2 Induces Mitochondrial Priming By Facilitating Perinuclmentioning

confidence: 99%

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

et al. 2016

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“…Increasing evidence demonstrates that the autophagy receptor protein p62/SQSTM1 is mainly mediated through ULK1 in response to energetic stress [45]. In addition, it is known that AKT regulates ULK1 during the process of autophagy, which is also regulated by AMPK [18,20].…”

Section: Discussionmentioning

confidence: 99%

Peiminine Inhibits Glioblastoma in Vitro and in Vivo Through Cell Cycle Arrest and Autophagic Flux Blocking

Zhao¹,

Shen²,

Zheng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumour in adults, with poor survival rate and high mortality rates. Existing treatments do not provide substantial benefits to patients; therefore, novel treatment strategies are required. Peiminine, a natural bioactive compound extracted from the traditional Chinese medicine Fritillaria thunbergii, has many pharmacological effects, especially anticancer activities. However, its anticancer effects on GBM and the underlying mechanism have not been demonstrated. This study was conducted to investigate the potential antitumour effects of peiminine in human GBM cells and to explore the related molecular signalling mechanisms in vitro and in vivo Methods: Cell viability and proliferation were detected with MTT and colony formation assays. Morphological changes associated with autophagy were assessed by transmission electron microscopy (TEM). The cell cycle rate was measured by flow cytometry. To detect changes in related genes and signalling pathways in vitro and in vivo, RNA-seq, Western blotting and immunohistochemical analyses were employed. Results: Peiminine significantly inhibited the proliferation and colony formation of GBM cells and resulted in changes in many tumour-related genes and transcriptional products. The potential anti-GBM role of peiminine might involve cell cycle arrest and autophagic flux blocking via changes in expression of the cyclin D1/CDK network, p62 and LC3. Changes in Changes in flow cytometry results and TEM findings were also observed. Molecular alterations included downregulation of the expression of not only phospho-Akt and phospho-GSK3β but also phospho-AMPK and phospho-ULK1. Furthermore, overexpression of AKT and inhibition of AKT reversed and augmented peiminine-induced cell cycle arrest in GBM cells, respectively. The cellular activation of AMPK reversed the changes in the levels of protein markers of autophagic flux. These results demonstrated that peiminine mediates cell cycle arrest by suppressing AktGSk3β signalling and blocks autophagic flux by depressing AMPK-ULK1 signalling in GBM cells. Finally, peiminine inhibited the growth of U251 gliomas in vivo. Conclusion: Peiminine inhibits glioblastoma in vitro and in vivo via arresting the cell cycle and blocking autophagic flux, suggesting new avenues for GBM therapy.

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“…Our results showed Ad-Sesn2 directly increased LC3-II expression and that eupatilin-mediated LC3-II expression was abolished by si-Sesn2, which also support the notion that Sesn2 activates autophagy. Recently, Ro et al [48] suggested that Sesn2 directly promotes ULK1-dependent autophagic degradation. In accordance with these studies, our supplemental data showed that Ad-Sesn2 promoted the phosphorylations of AMPKa and ULK1.…”

Section: Discussionmentioning

confidence: 99%

Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress

Jegal

Park

et al. 2016

Apoptosis

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Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) has many pharmacological activities including anti-inflammation, anti-oxidant and anti-cancer effects. Autophagy is the basic cellular machinery involving the digestion of damaged cellular components. In the present study, we investigated the protection effects of eupatilin against arachidonic acid (AA) and iron-induced oxidative stress in HepG2 cells and tried to elucidate the molecular mechanisms responsible. Eupatilin increased cell viability against AA + iron in a concentration-dependent manner and prevented mitochondrial dysfunction and reactive oxygen species (ROS) production. In addition, AA + iron increased the levels of pro-apoptotic proteins and these changes were prevented by eupatilin. Eupatilin also induced autophagy, as evidenced by the accumulation of microtubule-associated protein 1 light chain3-II and the detection of autophagic vacuoles. Furthermore, the protective effects of eupatilin on mitochondrial dysfunction and ROS production were significantly abolished by autophagy inhibitors. Eupatilin also increased the mRNA level of sestrin-2 and its promoter-driven reporter gene activity, which resulted in the up-regulation of sestrin-2 protein. Finally, gene silencing using sestrin-2 siRNA and the ectopic expression of recombinant adenoviral sestrin-2 indicated that sestrin-2 induction by eupatilin was required for autophagy-mediated cytoprotection against AA + iron. Our results suggest that eupatilin activates sestrin-2-dependent autophagy, thereby preventing oxidative stress induced by AA + iron.

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Sestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1

Cited by 100 publications

References 44 publications

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

Peiminine Inhibits Glioblastoma in Vitro and in Vivo Through Cell Cycle Arrest and Autophagic Flux Blocking

Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress

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