Active Caspase-1 Is a Regulator of Unconventional Protein Secretion

Keller, Martin; Rüegg, Andreas; Werner, Sabine; Beer, Hans‐Dietmar

doi:10.1016/j.cell.2007.12.040

Cited by 781 publications

(699 citation statements)

References 49 publications

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“…Keratinocytes express large amounts of pro-IL-1a, which is biologically active without further processing. It is released upon cell lysis and can be secreted after inflammasome activation 39,44 . IL-1 can act in an autocrine manner, and its release by dying keratinocytes can stimulate further IL-1 production 39 .…”

Section: Discussionmentioning

confidence: 99%

Aldara activates TLR7-independent immune defence

et al. 2013

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Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.

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Section: Discussionmentioning

confidence: 99%

Aldara activates TLR7-independent immune defence

et al. 2013

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“…Caspase-1 is the enzyme responsible for the maturation and release of IL-1b and IL-18. It is worth noting that caspase-1 also participates in the secretion of IL-1a, biologically active without any need for proteolytic processing [18]. Alum activated NLRP3 directly upon phagocytosis [14,17] without any intermediary role for the danger signals MSU and ATP [14,15,17].…”

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confidence: 99%

The controversial relationship between NLRP3, alum, danger signals and the next‐generation adjuvants

2010

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Alum has been the only adjuvant licensed for human vaccines for decades and is still widely used, but its mechanism of action remains obscure. Recently, the NLRP3 inflammasome has been linked to the immunostimulatory properties of alum and other particulate adjuvants, although it is disputed to what degree NLRP3 is genuinely essential in vivo. Meanwhile, researchers are testing adjuvants harnessing both the infectious/non‐infectious‐discriminating TLR and the danger‐sensing NLRP3 inflammasome pathways. Could this be the basis of a long‐needed rationale in the design of adjuvants?

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“…Brefeldin A treatment did not inhibit PARK7 secretion (Figure 2(C)), confirming that 6-OHDA-induced PARK7 secretion was mediated via an ER-/Golgi-independent secretory pathway. Because it had recently been reported that CASP1 (caspase 1) may act as regulator of unconventional protein secretion [34], we decided to assess the respective effects of a pan-caspase inhibitor (zVAD; i.e., Z-VAD[OMe]-FMK) and a specific CASP1 inhibitor (YVAD; i.e., Ac-YVAD-CMK) on PARK7 secretion. Our results indicated that 6-OHDA-induced PARK7 secretion was inhibited by either inhibitor (Figure 2(D)).…”

Section: Resultsmentioning

confidence: 99%

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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Active Caspase-1 Is a Regulator of Unconventional Protein Secretion

Cited by 781 publications

References 49 publications

Aldara activates TLR7-independent immune defence

Aldara activates TLR7-independent immune defence

The controversial relationship between NLRP3, alum, danger signals and the next‐generation adjuvants

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

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