Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

Saitoh, Tatsuya; Fujita, Naonobu; Hayashi, T.; Takahara, Keigo; Satoh, Takashi; Lee, Hanna; Matsunaga, Kohichi; Kageyama, Shun; Omori, Hiroko; Noda, Tetsuji; Yamamoto, Naoki; Kawai, Taro; Ishii, Ken J.; Takeuchi, Osamu; Yoshimori, Tamotsu; Akira, Shizuo

doi:10.1073/pnas.0911267106

Cited by 728 publications

(712 citation statements)

References 36 publications

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“…Results for atg5 -/- MEF cells indicated that there was no LC3B-II formation and that 6-OHDA did not induce PARK7 secretion (Figure 5(A)). We further employed Atg9 -deficient ( atg9 -/- ) and Atg16l1 -deficient ( atg16l1 -/- ) MEF cells, in both of which autophagosome formation was impaired [43,44]. Consistent with the results obtained for atg5 -/- MEF cells, 6-OHDA-induced PARK7 secretion and LC3B-II formation were each suppressed in both atg9 -/- MEF cells (Figure 5(B)) and atg16l1 -/- MEF cells (Figure 5(C)).…”

Section: Resultsmentioning

confidence: 99%

“…WT MEF and atg5 −/- MEF cells [42] were kindly provided by Dr. Noboru Mizushima (The University of Tokyo). The atg9 −/- MEF and atg16l1 −/- MEF cells [43,44] were kindly provided by Dr. Shizuo Akira (Osaka University). Cells were maintained in Dulbecco’s Modified Eagle’s Medium/Nutrient Mixture F-12 (DMEM/F12; Thermo Fisher Scientific, 11320–033), to which 10% fetal bovine serum (Hyclone, SH30370.03) and antibiotics (100 U/ml penicillin, 100 μg/ml streptomycin; Thermo Fisher Scientific, 15140122) had been added.…”

Section: Methodsmentioning

confidence: 99%

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6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

et al. 2018

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PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear. In the present study, we found that PARK7 secretion was increased by treatment with 6-OHDA via the unconventional secretory pathway in human neuroblastoma SH-SY5Y cells and MEF cells. We also found that 6-OHDA-induced PARK7 secretion was suppressed in Atg5-, Atg9-, or Atg16l1-deficient MEF cells or ATG16L1 knockdown SH-SY5Y cells, indicating that the autophagy-based unconventional secretory pathway is involved in PARK7 secretion. We moreover observed that 6-OHDA-derived electrophilic quinone induced oxidative stress as indicated by a decrease in glutathione levels, and that this was suppressed by pretreatment with antioxidant NAC. We further found that NAC treatment suppressed autophagy and PARK7 secretion. We also observed that 6-OHDA-induced autophagy was associated with activation of AMPK and ULK1 via a pathway which was independent of MTOR. Collectively these results suggest that electrophilic 6-OHDA quinone enhances oxidative stress, and that this is followed by AMPK-ULK1 pathway activation and induction of secretory autophagy to produce unconventional secretion of PARK7.Abbreviations: 6-OHDA: 6-hydroxydopamine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CAV1: caveolin 1; ER: endoplasmic reticulum; FN1: fibronectin 1; GSH: glutathione; IDE: insulin degrading enzyme; IL: interleukin; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARK7/DJ-1: Parkinsonism associated deglycase; PD: Parkinson disease; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; RPN1: ribophorin I; ROS: reactive oxygen species; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

et al. 2018

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“…This down regulation of the innate immune response was independent of autophagy because the puncta enclosing STING did not have the morphological characteristics of autophagosome. Atg9 knockout MEFs showed enhanced association of TBK1 with STING (Saitoh et al, 2009). Thus, in addition to down regulation via ubiquitination, Atg9 and other autophagosome-related proteins seem to negatively regulate STING mediated innate response to dsDNA by an unknown mechanism.…”

Section: Proteinmentioning

confidence: 99%

“…In addition, proteins involved in autophagy have also been shown to have an impact on the innate immune signaling by STING (Saitoh et al, 2009). More recently, an exo-nuclease, TREX1 has been shown to indirectly regulate the activity of STING (Yan et al, 2010).…”

Section: Regulation Of Stingmentioning

confidence: 99%

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Binding of bacterial secondary messenger molecule c di-GMP is a STING operation

2012

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Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

Luo

Shu

2017

FEBS Letters

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Edited by Wilhelm JustRhomboid-like pseudoproteases are a conserved superfamily of proteins related to the rhomboid intramembrane serine proteases that lack key catalytic residues. iRhom2, a member of the rhomboid-like pseudoprotease superfamily, regulates the maturation and trafficking of ADAM17 and is associated with inflammatory arthritis. Recent studies demonstrate that iRhom2 is also involved in innate immunity by regulating the trafficking and stability of MITA (also called STING), which is a central adaptor in innate antiviral signalling pathways. Here, we summarize recent progress on the roles and mechanisms of iRhom2 and its homologues in innate immunity and also discuss the links between the physiological functions of iRhoms and immunological diseases.

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Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

Cited by 728 publications

References 36 publications

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

Binding of bacterial secondary messenger molecule c di-GMP is a STING operation

Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

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