Nondegradative Role of Atg5-Atg12/ Atg16L1 Autophagy Protein Complex in Antiviral Activity of Interferon Gamma

Hwang, Seungmin; Maloney, Nicole S.; Bruinsma, Monique W.; Goel, Gautam; Duan, Erning; Zhang, Lei; Shrestha, Bimmi; Diamond, Michael S.; Dani, Adish; Sosnovtsev, Stanislav V.; Green, Kim Y.; López-Otı́n, Carlos; Xavier, Ramnik J.; Thackray, Larissa B.; Virgin, Herbert W.

doi:10.1016/j.chom.2012.03.002

Cited by 229 publications

(313 citation statements)

References 46 publications

(95 reference statements)

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“…Furthermore, Atg7 and Atg16L1 are essential for the IFN-g-induced nonautophagic antiviral response (18). Given that GBPs, another group of IFN-ginducible GTPases, critically control IFN-g-mediated intracellular elimination of T. gondii in cooperation with Irgb6 in mice (12), Atg7 and Atg16L1, in addition to Atg5, may be integral to the recruitment of Irgb6 and GBPs to T. gondii for clearance.…”

Section: Discussionmentioning

confidence: 99%

“…Myeloid-specific ablation of Atg5 in mice culminated in decreased recruitment of an IRG to T. gondii in IFN-g-activated macrophages and led to high parasite susceptibility in vivo. Furthermore, other autophagy proteins, such as Atg7 and Atg16L1, were recently shown to play a nondegradative role in the IFN-g-mediated antiviral programs against murine norovirus (18), prompting us to explore the functions of autophagy proteins other than Atg5 in the IFN-g-mediated anti-T. gondii cellular innate immune responses.…”

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confidence: 99%

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Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

Ohshima

Lee

Sasai

et al. 2014

The Journal of Immunology

112

127

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IFN-γ mediates cellular innate immunity against an intracellular parasite, Toxoplasma gondii, by inducing immunity-related GTPases such as p47 IFN-γ–regulated GTPases (IRGs) and p65 guanylate-binding proteins (GBPs), which also participate in antibacterial responses via autophagy. An essential autophagy protein, Atg5, was previously shown to play a critical role in anti–T. gondii cell-autonomous immunity. However, the involvement of other autophagy proteins remains unknown. In this study, we show that essential autophagy proteins differentially participate in anti–T. gondii cellular immunity by recruiting IFN-γ–inducible GTPases. IFN-γ–induced suppression of T. gondii proliferation and recruitment of an IRG Irgb6 and GBPs are profoundly impaired in Atg7- or Atg16L1-deficient cells. In contrast, cells lacking other essential autophagy proteins, Atg9a and Atg14, are capable of mediating the anti–T. gondii response and recruiting Irgb6 and GBPs to the parasites. Although IFN-γ also stimulates anti–T. gondii cellular immunity in humans, whether this response requires GBPs and human autophagy proteins remains to be seen. To analyze the role of human ATG16L1 and GBPs in IFN-γ–mediated anti–T. gondii responses, human cells lacking ATG16L1 or GBPs were generated by the Cas9/CRISPR genome-editing technique. Although both ATG16L1 and GBPs are dispensable for IFN-γ–induced inhibition of T. gondii proliferation in the human cells, human ATG16L1 is also required for the recruitment of GBPs. Taken together, human ATG16L1 and mouse autophagy components Atg7 and Atg16L1, but not Atg9a and Atg14, participate in the IFN-γ–induced recruitment of the immunity-related GTPases to the intracellular pathogen.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

Ohshima

Lee

Sasai

et al. 2014

The Journal of Immunology

112

127

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“…[13][14][15][16] To rule out this possibility, we examined how macrophage-specific deletion of genes involved in the initiation of autophagy (Rb1cc1 and Atg14), and in autophagosome formation (Atg16l1, Atg7 and Atg3) affected the severity of uveitis using the LPS-based EIU model. As shown in Figure 3, macrophage-specific deletion of each of these genes significantly increased the severity of uveitis compared to floxed littermate controls in the EIU model, while no evidence of uveitis could be detected in vehicle-treated mice (Fig.…”

Section: Autophagy In Macrophages Regulates the Severity Of Uveitismentioning

confidence: 99%

“…Atg5 CKO and littermate floxed control mice 6 to 8 wk of age were injected with an emulsion of 200 mg of human RBP3 fragment (RBP3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] ; Anaspec, AS62297) in 200 ml of complete Freund Adjuvant (1:1 v/v) (BD Difco, 263810) supplemented with 2.5 mg/mL Mycobacterium tuberculosis strain H37RA (BD Difco, 231141). The dose was dispersed subcutaneously in equal volumes into each thigh and the base of the tail.…”

Section: Experimental Autoimmune Uveitismentioning

confidence: 99%

Impaired autophagy in macrophages promotes inflammatory eye disease

et al. 2016

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Autophagy is critical for maintaining cellular homeostasis. Organs such as the eye and brain are immunologically privileged. Here, we demonstrate that autophagy is essential for maintaining ocular immune privilege. Deletion of multiple autophagy genes in macrophages leads to an inflammation-mediated eye disease called uveitis that can cause blindness. Loss of autophagy activates inflammasome-mediated IL1B secretion that increases disease severity. Inhibition of caspase activity by gene deletion or pharmacological means completely reverses the disease phenotype. Of interest, experimental uveitis was also increased in a model of Crohn disease, a systemic autoimmune disease in which patients often develop uveitis, offering a potential mechanistic link between macrophage autophagy and systemic disease. These findings directly implicate the homeostatic process of autophagy in blinding eye disease and identify novel pathways for therapeutic intervention in uveitis.

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“…The antiviral activity of IFN-c against murine norovirus requires several autophagy proteins such as Atg5-12, 7, and 16, but it does not require induction of autophagy (62). Complex formation of autophagy proteins including ATG5-12/ATG16L1 can exert a nondegradative role in IFN-c-mediated antiviral defenses (62).…”

Section: Autophagy Proteins and Innate Immune Signalingmentioning

confidence: 99%

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

Nakahira

Cloonan

Mizumura

et al. 2014

Antioxidants & Redox Signaling

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Significance: Autophagy is a fundamental cellular process that functions in the turnover of subcellular organelles and protein. Activation of autophagy may represent a cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Autophagy can increase survival during nutrient deficiency and play a multifunctional role in host defense, by promoting pathogen clearance and modulating innate and adaptive immune responses. Recent Advances: Autophagy has been described as an inducible response to oxidative stress. Once believed to represent a random process, recent studies have defined selective mechanisms for cargo assimilation into autophagosomes. Such mechanisms may provide for protein aggregate detoxification and mitochondrial homeostasis during oxidative stress. Although long studied as a cellular phenomenon, recent advances implicate autophagy as a component of human diseases. Altered autophagy phenotypes have been observed in various human diseases, including lung diseases such as chronic obstructive lung disease, cystic fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis. Critical Issues: Although autophagy can represent a pro-survival process, in particular, during nutrient starvation, its role in disease pathogenesis may be multifunctional and complex. The relationship of autophagy to programmed cell death pathways is incompletely defined and varies with model system. Future Directions: Activation or inhibition of autophagy may be used to alter the progression of human diseases. Further resolution of the mechanisms by which autophagy impacts the initiation and progression of diseases may lead to the development of therapeutics specifically targeting this pathway. Antioxid. Redox Signal. 20,

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Nondegradative Role of Atg5-Atg12/ Atg16L1 Autophagy Protein Complex in Antiviral Activity of Interferon Gamma

Cited by 229 publications

References 46 publications

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

Role of Mouse and Human Autophagy Proteins in IFN-γ–Induced Cell-Autonomous Responses against Toxoplasma gondii

Impaired autophagy in macrophages promotes inflammatory eye disease

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

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