IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion

Gkirtzimanaki, Katerina; Kabrani, Eleni; Nikoleri, Dimitra; Polyzos, Alexander; Blanas, Athanasios; Sidiropoulos, Prodromos; Makrigiannakis, Antonis; Βertsias, George; Boumpas, Dimitrios T.; Verginis, Panayotis

doi:10.1016/j.celrep.2018.09.001

Cited by 105 publications

(88 citation statements)

References 62 publications

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“…Autophagy deficiency results in the accumulation of dysfunctional mitochondria that are the major source of DAMPs for activation of cGAS-STING and RIG-I/MAVS signaling pathways. Activations of these pathways lead to robust induction of interferon response resulting in antiviral response or autoimmune diseases (Gkirtzimanaki et al, 2018;Sliter et al, 2018;Tal et al, 2009;Xu et al, 2019). Others and we have found that IRGM is a key autophagy protein that plays a significant role in anti-bacterial autophagy and autophagy of inflammasomes (Chauhan et al, 2015;Kumar et al, 2018;Mehto et al, 2019;Singh et al, 2006;Singh et al, 2010).…”

Section: Introductionmentioning

confidence: 80%

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Mehto

Nath

et al. 2019

Preprint

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Activation of type 1 interferon response is extensively connected with the antiviral immunity and pathogenesis of autoimmune diseases. Here, we found that IRGM, whose deficiency is linked with the genesis of several autoimmune disorders, is a master negative regulator of the interferon response. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their autophagic degradation to restrain activation of interferon signaling. Further, IRGM maintains mitophagy flux, and its deficiency results in the accumulation of defunct leaky mitochondria that releases cytosolic DAMPs triggering activation of interferon responses via cGAS-STING and RIG-I-MAVS signaling axis. Due to an enduring type 1 IFN response in IRGM-deficient cells and mice, they were intrinsically resistant to infection of the Japanese Encephalitis virus, Herpes Simplex virus, and Chikungunya virus. Altogether, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases. Further, it identifies IRGM as a broad therapeutic target for defense against viruses.

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Section: Introductionmentioning

confidence: 80%

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Mehto

Nath

et al. 2019

Preprint

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“…IFN-α also exerts stimulatory effects on the adaptive immune system by enhancing B cell differentiation and survival of autoimmune B cells [43,44]. Moreover, IFN-α impairs autophagic degradation of mtDNA and vasculogenesis in SLE, serving as a drug target [45,46]. IFN-α is encoded by IFNA1 that is a target gene of miR-181b [13].…”

Section: Discussionmentioning

confidence: 99%

Interaction of miR-181b and IFNA1 Polymorphisms on the Risk of Systemic Lupus Erythematosus

Yang

Zeng

Shi

2020

BioMed Research International

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Introduction. A previous work has discovered that chromosome 1q32 locus linked to the risk of systemic lupus erythematosus (SLE) and miR-181b located on the susceptibility site with downregulation inversely correlating to its target molecular interferon alpha 1 (IFNA1). The purpose of this study was to investigate the association of miR-181b and IFNA1 polymorphisms with IS risk. Methods. The miR-181b rs322931, IFNA1 rs1332190, and rs10811543 were genotyped using a Multiplex SNaPshot assay. miR-181b expression levels in plasma of SLE patients and controls were analyzed using quantitative PCR. Results. The rs322931 CT, CT/TT, and T allele exerted an increased trend of SLE risk (CT vs. CC: adjusted OR=1.71, 95% CI 1.16-2.50, P=0.01; CT/TT vs. CC: adjusted OR=1.45, 95% CI 1.08-1.95, P=0.01; T vs. C: adjusted OR=1.38, 95% CI 1.07-1.79, P=0.01). Combined genotypes of the rs322931 CT/TT+rs1332190 TT and the rs322931 CC+rs10811543 AG/AA also revealed an increased risk of SLE. Gene-gene interaction analysis showed that a three-locus model consisting of rs322931, rs1332190, and rs10811543 attributed an increased risk of SLE. Further genotype-phenotype analysis revealed that rs322931 CT/TT carriers displayed lower levels of miR-181b. Conclusions. These findings indicate that the miR-181b rs322931 may be singly and jointly responsible for the etiology of SLE by altering miR-181b expression.

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“…Similarly, mTOR-dependent autophagy impairment was documented within SLE monocytes following sustained inflammatory stimuli such as IFNα. This, in turn, is associated with enhanced mitochondrial damage, oxidative stress and accumulation of undigested mitochondrial DNA (mtDNA) which is released extracellularly to trigger anti-DNA autoimmunity [101]. Accordingly, polymorphisms in the ATG5 gene are associated with disease susceptibility in SLE patients, with the rs2245214 polymorphism being significantly associated with a higher risk of producing anti-DNA autoantibodies [102].…”

Section: Antiphospholipid Syndrome and Systemic Lupus Erythematosusmentioning

confidence: 99%

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

Limanaqi

Biagioni

Busceti

et al. 2020

IJMS

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Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.

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IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion

Cited by 105 publications

References 62 publications

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways

Interaction of miR-181b and IFNA1 Polymorphisms on the Risk of Systemic Lupus Erythematosus

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

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