UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1)

Kemp, Michael G.; Lindsey-Boltz, Laura A.; Sancar, Aziz

doi:10.1074/jbc.m115.649301

Cited by 51 publications

(38 citation statements)

References 54 publications

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“…Reports regarding ULK1 in keratinocytes are rare. Recently, Akinduro et al [80] reported that differentiating keratinocytes depleted of ULK1 lacked nucleophagy, and Kemp et al [81] found that ULK1 signaling was deregulated by UV induced DNA damage. Our result is in accordance with the findings of Kemp et al, because we observed that ULK1 and its phosphorylation were inhibited after UVB stimulation.…”

Section: Discussionmentioning

confidence: 99%

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

et al. 2017

Oxidative Medicine and Cellular Longevity

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The mechanistic target of Rapamycin (MTOR) protein is a crucial signaling regulator in mammalian cells that is extensively involved in cellular biology. The function of MTOR signaling in keratinocytes remains unclear. In this study, we detected the MTOR signaling and autophagy response in the human keratinocyte cell line HaCaT and human epidermal keratinocytes treated with MTOR inhibitors. Moreover, we detected the impact of MTOR inhibitors on keratinocytes exposed to the common carcinogenic stressors ultraviolet B (UVB) and UVA radiation. As a result, keratinocytes were sensitive to the MTOR inhibitors Rapamycin, everolimus, Torin 1, and pp242, but the regulation of MTOR downstream signaling was distinct. Next, autophagy induction only was observed in HaCaT cells treated with Rapamycin. Furthermore, we found that MTOR signaling was insensitive to UVB but sensitive to UVA radiation. UVB treatment also had no impact on the inhibition of MTOR signaling by MTOR inhibitors. Finally, MTOR inhibition by Rapamycin, everolimus, or pp242 did not affect the series of biological events in keratinocytes exposed to UVB, including the downregulation of BiP and PERK, activation of Histone H2A and JNK, and cleavage of caspase-3 and PARP. Our study demonstrated that MTOR inhibition in keratinocytes cannot always induce autophagy, and the MTOR pathway does not play a central role in the UVB triggered cellular response.

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Section: Discussionmentioning

confidence: 99%

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…The ATG proteins in keratinocytes remain to be clarified for their expression regulation, protein-protein interaction, roles in autophagic machinery and extended functions. Recently, Kemp et al reported that ULK1 is deregulated due to the UV-induced DNA damage in keratinocytes, which caused a stimulator of interferon genes (STING)-dependent interferon regulatory factor 3 (IRF3) activation, suggesting the function of ULK1 in immune response [115]. Besides the autophagy regulation, ATG proteins perform other biological functions such as inflammation, immunity and efferocytosis.…”

Section: Discussionmentioning

confidence: 99%

The signaling involved in autophagy machinery in keratinocytes and therapeutic approaches for skin diseases

Chen

2016

Oncotarget

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Autophagy is responsible for the lysosomal degradation of proteins, organelles, microorganisms and exogenous particles. Epidermis primarily consists of keratinocytes which functions as an extremely important barrier. Investigation on autophagy in keratinocytes has been continuously renewing, but is not so systematic due to the complexity of the autophagy machinery. Here we reviewed recent studies on the autophagy in keratinocyte with a focus on interplay between autophagy machinery and keratinocytes biology, and novel autophagy regulators identified in keratinocytes. In this review, we discussed the roles of autophagy in apoptosis, differentiation, immune response, survival and melanin metabolism, trying to reveal the possible involvement of autophagy in skin aging, skin disorders and skin color formation. Since autophagy routinely plays a double-edged sword role in various conditions, its functions in skin homeostasis and potential application as a therapeutic target for skin diseases remains to be clarified. Furthermore, more investigations are needed on optimizing designed strategies to inhibit or enhance autophagy for clinical efficacy.

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“…71 Because ULK1 is required to initiate autophagosome formation, the premature degradation of ULK1 by UV-induced apoptotic signaling might be expected to prevent proper activation of the STING pathway. Similarly, the transient nature of the STING signaling pathway following the introduction of DNA or cyclic dinucleotides into the cytosol would mean that a delayed loss of ULK1 would occur too late to affect the rapid cellular response to STING ligands.…”

Section: Environmental Genotoxins and The Interplay Between Apoptosismentioning

confidence: 99%

Crosstalk Between Apoptosis and Autophagy: Environmental Genotoxins, Infection, and Innate Immunity

Kemp

2017

J�Cell Death

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Autoimmune disorders constitute a major and growing health concern. However, the genetic and environmental factors that contribute to or exacerbate disease symptoms remain unclear. Type I interferons (IFNs) are known to break immune tolerance and be elevated in the serum of patients with autoimmune diseases such as lupus. Extensive work over the past decade has characterized the role of a protein termed stimulator of interferon genes, or STING, in mediating IFN expression and activation in response to cytosolic DNA and cyclic dinucleotides. Interestingly, this STING-dependent innate immune pathway both utilizes and is targeted by the cell’s autophagic machinery. Given that aberrant interplay between the apoptotic and autophagic machineries contributes to deregulation of the STING-dependent pathway, IFN-regulated autoimmune phenotypes may be influenced by the combined exposure to environmental carcinogens and pathogenic microorganisms and viruses. This review therefore summarizes recent data regarding these important issues in the field of autoimmunity.

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UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1)

Cited by 51 publications

References 54 publications

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

The signaling involved in autophagy machinery in keratinocytes and therapeutic approaches for skin diseases

Crosstalk Between Apoptosis and Autophagy: Environmental Genotoxins, Infection, and Innate Immunity

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