ß&lt;sub&gt;3&lt;/sub&gt;-Integrin Inhibits Lipopolysaccharide-Induced Autophagy in Cardiomyocytes via the Akt Signaling Pathway

Zhu, Ying; Li, Li; Gong, Sitang; Yu, Yan; Dai, Hailu; Cai, Guolong; Yan, Junkai

doi:10.1159/000371489

Cited by 13 publications

(10 citation statements)

References 31 publications

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“…From a more general perspective, an inverse relationship between autophagy and integrin-dependent anchorage signalling has been proposed, implying that the autophagic machinery counteracts anoikis (detachment-induced apoptosis) (57). For instance, downregulation of integrin b3 resulted in upregulation of autophagy markers (58). In line, it was observed that blockage of aVb3 signalling results in inhibition of adhesion and concomitant activation of the autophagic machinery, manifested in increased MAP1LC3B expression (59).…”

Section: Functional Lir Motifs In Integrin B3 As Potential Linkage Ofmentioning

confidence: 87%

Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

Kliche

Ali

Ivarsson

2020

Preprint

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The spike protein of the SARS-CoV-2 interacts with angiotensin converting enzyme 2 (ACE2) and enters the host cell by receptor-mediated endocytosis. Concomitantly, evidence is pointing to the involvement of additional host cell receptors, such as integrins. The cytoplasmic tails of ACE2 and integrin β3 contain a plethora of predicted binding motifs. Here, we confirm the functionality of some of these motifs through affinity measurements. The class I PDZ binding motif in the ACE2 cytoplasmic tail binds the first PDZ domain of the scaffold protein NHERF3. The clathrin-adaptor subunit AP2 μ2 interacts with an endocytic motif in the ACE2 with low affinity and the interaction is abolished by phosphorylation of Tyr781. Furthermore, the C-terminal region of integrin b3 contains a LC3-interacting region, and its interaction with ATG8 domains is enhanced by phosphorylation. Together, our data provides possible molecular links between host cell receptors and endocytosis and autophagy.One sentence summaryAffinity measurements confirmed binding of short linear motifs in the cytoplasmic tails of ACE2 and integrin β3, thereby linking the receptors to endocytosis and autophagy.

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Section: Functional Lir Motifs In Integrin B3 As Potential Linkage Ofmentioning

confidence: 87%

Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

Kliche

Ali

Ivarsson

2020

Preprint

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“…This indicates PI3K-Akt-mTOR signaling or similar pathways may be activated when integrin β3 is overexpressed. Studies have shown that integrin β3 upregulation inhibits the autophagic process in cardiomyocytes by activating Akt [41], suggesting that the expression status of integrin may affect cell autophagy.…”

Section: Discussionmentioning

confidence: 99%

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Wan

Xie

et al. 2019

Laboratory Investigation

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ARTICLEThy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis Abstract Lipopolysaccharide (LPS)-induced autophagy inhibition in lung fibroblasts is closely associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) pathway. However, the underlying mechanism remains unknown. In this study, we demonstrated that LPS activated the PI3K-Akt-mTOR pathway and inhibited lung fibroblast autophagy by depleting thymocyte differentiation antigen-1 (Thy-1) and upregulating integrin β3 (Itgb3). Challenge of the human lung fibroblast MRC-5 cell line with LPS resulted in significant upregulation of integrin β3, activation of the PI3K-Akt-mTOR pathway and inhibition of autophagy, which could be abolished by integrin β3 silencing by specific shRNA or treatment with the integrin β3 inhibitor cilengitide. Meanwhile, LPS could inhibit Thy-1 expression accompanied with PI3K-Akt-mTOR pathway activation and lung fibroblast autophagy inhibition; these effects could be prevented by Thy-1 overexpression. Meanwhile, Thy-1 downregulation with Thy-1 shRNA could mimic the effects of LPS, inducing the activation of PI3K-Akt-mTOR pathway and inhibiting lung fibroblast autophagy. Furthermore, protein immunoprecipitation analysis demonstrated that LPS reduced the binding of Thy-1 to integrin β3. Thy-1 downregulation, integrin β3 upregulation and autophagy inhibition were also detected in a mouse model of LPS-induced pulmonary fibrosis, which could be prohibited by intratracheal injection of Thy-1 overexpressing adeno-associated virus (AAV) or intraperitoneal injection of the integrin β3 inhibitor cilengitide. In conclusion, this study demonstrated that Thy-1 depletion and integrin β3 upregulation are involved in LPS-induced pulmonary fibrosis, and may serve as potential therapeutic targets for pulmonary fibrosis.

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“…Lipopolysaccharide (LPS) is a major outer membrane component of Gram-negative bacteria such as E. coli, and acts as a mediator of host responses that elicit intestinal endotoxemia and multiple organ failure, as well as a stimulator of autophagic signaling in cultured intestinal epithelial cells and other cell types [39,40]. Under normal physiological conditions, low levels of autophagy are maintained that play a vital role in host defenses against microbial infection [41].…”

Section: Discussionmentioning

confidence: 99%

The Role of Probiotics in Lipopolysaccharide-Induced Autophagy in Intestinal Epithelial Cells

Han

Zhang

Shi

et al. 2016

Cell Physiol Biochem

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Background/Aims: Dysfunction of autophagy has been associated with loss of intestinal homeostasis. Lipopolysaccharide (LPS) from Gram-negative bacteria is known to be a major initiator of intestinal epithelial cell (IEC) autophagy. Although probiotics have been recognized to be involved in many therapeutic properties and participate in host defense responses, the molecular mechanisms by which probiotics exert these positive effects remain unknown. This study assessed the effect of probiotics on LPS-induced physical barrier dysfunction and the underlying mechanism of probiotic action in IECs with a focus on autophagy. Methods: A LPS-induced autophagic model was established in rat IEC18 cells wherein cells were treated with culture medium supernatants of Bifidobacteria following LPS intervention at indicated times. Autophagosomes in IEC18 cells were visualized by confocal microscopy after transfection with a tandem GFP-mCherry-LC3 construct and also by transmission electron microscopy. Autophagy-associated protein levels were analyzed by western blot and transepithelial electrical resistance (TEER) was measured using an epithelial voltohmmeter. Results: Probiotic treatment could effectively inhibit LPS-induced autophagy, as evidenced by the decreased ratio of microtubule-associated light chain 3 (LC3)-II/LC3-I, fewer autophagic vacuoles, and reduced punctate distribution of GFP-mCherry-LC3. In addition, probiotics prevented chloroquine (CQ) inhibition of autophagic flux and autophagolysosomal fusion as indicated by a failure to recruit LAMP1 and cathepsin D to lysosomes. Interestingly, ATG16L1 knockdown did not inhibit the effect of probiotics on LPS-induced autophagy. Furthermore, the diminished barrier function could be prevented by probiotics. Conclusions: We provide evidence that autophagy mediation by probiotics may be involved in enteroprotection against LPS-induced intestinal epithelial toxicity, and could serve as a novel mechanism through which probiotics promote and maintain gut homeostasis.

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ß<sub>3</sub>-Integrin Inhibits Lipopolysaccharide-Induced Autophagy in Cardiomyocytes via the Akt Signaling Pathway

Cited by 13 publications

References 31 publications

Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

Cytoplasmic short linear motifs in ACE2 and integrin β3 link SARS-CoV-2 host cell receptors to endocytosis and autophagy

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

The Role of Probiotics in Lipopolysaccharide-Induced Autophagy in Intestinal Epithelial Cells

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