Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria

Singh, Sudha; Ornatowski, Wojciech; Vergne, Isabelle; Naylor, John; Delgado, Mònica; Roberts, Esteban; Ponpuak, Marisa; Master, Sharon; Pilli, Manohar; White, Eileen; Komatsu, Masaaki; Deretic, Vojo

doi:10.1038/ncb2119

Cited by 225 publications

(251 citation statements)

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“…Nevertheless, our results suggest that the punctate mitochondrial morphology seen in Irgm1-deficient cells is secondary to accumulation of LC-AC in those cells, because treatment of the cells with fatty acid synthase inhibitors to reduce fatty acid concentrations not only blunted RANTES production in IFN-␥-primed, Irgm1-deficient macrophages, it also eliminated the punctate mitochondrial phenotype. This notion is contrary to previous studies that have suggested a direct role for Irgm1 in both associating with the mitochondria and controlling their dynamics (20,21,25,27,78). Our ROS-quenching experiments using NAC suggest that ROS are probably required for the effect of Irgm1 deficiency on mitochondrial morphology and production of RANTES and MCP-1 in IFN-␥-primed Irgm1-deficient macrophages.…”

Section: Discussioncontrasting

confidence: 56%

“…Previous work has attributed the bacterial susceptibility in Irgm1-deficient mice to defective processing of bacteria-containing phagosomes in macrophages and other cells (5,15,(25)(26)(27). That reduced capacity to manifest IFN-␥-induced killing of S. typhimurium and Mycobacterium tuberculosis has been further linked to altered autophagic function in Irgm1-deficient macrophages (15,20,21,(27)(28)(29)(30). Impaired autophagy ostensibly leads to a reduced capacity to restrict bacterial growth, increased inflammation, and ultimately death of the host, although these linkages have not been formally established.…”

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confidence: 99%

“…Similar to the related guanylate-binding protein and Mx gene families, they encode large GTP-binding proteins that function as dynamin-like proteins in mediating membrane remodeling and trafficking processes in cells (1)(2)(3)(4). In the absence of certain IRG proteins, alterations in membrane remodeling events have been observed, including the processing of pathogen-containing vacuoles (5)(6)(7)(8), vesicle formation and transport (4, 8 -12), cell motility (13,14), autophagy (15)(16)(17)(18)(19)(20), and mitochondrial fission (20,21). How these alterations relate to the dysfunctional immune responses displayed in IRG-deficient cells and mice in response to a variety of pathogens remains unclear.…”

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confidence: 99%

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Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-␥ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-␥-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.

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Section: Discussioncontrasting

confidence: 56%

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confidence: 99%

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confidence: 99%

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Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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“…Their functions in the context of the male germline may indirectly contribute to proper reaction in the face of damage. For instance, IRGM, a member of the p47 immunity-related GTPases family, is a mediator of autophagy as part of a defense mechanism that acts on intracellular pathogens, 41,42 but is also involved in Crohn's disease, 43,44 a chronic inflammatory bowel disease. We propose that ERV9-LTR-mediated IRGM expression may also enhance the defense mechanisms of germ cells against intracellular pathogens and/or contributes to the regulation of inflammatory responses in the testes.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Beyer

Krönung

Leha³

et al. 2015

Cell Death Differ

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The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3' Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression.

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“…When the macrophages are stimulated and the pathogens are engulfed, their activation leads to the production of IRGM1, a GTPase involved in stimulation of INF-γ that is the key cytokine in inducing autophagy [21]. Singh and co-workers [22] have shown in their work that IRGM1 probably translocate in the mitochondrial to regulate the autophagy in association with mitochondrial fission. Mycobacteria have evolved a strategy to survive also to autophagy.…”

Section: Autophagymentioning

confidence: 99%

Macrophage Infection by Mycobacteria

Saleh¹

2016

Mycobact Dis

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Mycobacterium tuberculosis is the etiological agent of tuberculosis. It is a pathogen that continues to draw international concerns particularly due to the emergence of multi-drug resistance and to the difficulties associated with the diagnosis and treatment of latent tuberculosis. A key process in the pathogenesis of this disease is the interaction between this pathogen and host macrophages. Invasion of the macrophages protects the pathogen from attack by the immune system, allows it to multiply while protected within the macrophages, and alters the immune response as it influences the profiles of the cytokine and chemokine responses. Key to the intracellular survival of the pathogen within the macrophages is the specific interaction between the pathogen and its virulence factors with the host. This review provides an a summary of pertinent literature on the topic of macrophage receptors utilized by the pathogen, its survival strategies within the macrophage, and the general profile of immune signalling upon exposure to the pathogen. The importance of specific macrophage receptors and certain components of the pathogen to the direction of the immune response are also discussed.

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Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria

Cited by 225 publications

References 64 publications

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

Macrophage Infection by Mycobacteria

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