IRGM Governs the Core Autophagy Machinery to Conduct Antimicrobial Defense

Chauhan, Santosh; Mandell, Michael A.; Deretic, Vojo

doi:10.1016/j.molcel.2015.03.020

Cited by 201 publications

(223 citation statements)

References 48 publications

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“…It recently was found that in normal cells undergoing mitosis Golgi fragmentation is induced by AMPKα-dependent phosphorylation of GBF1 at T1337 (40,41). Another study showed that IRGM stimulates AMPKα by stabilization of the kinase in its T172 phosphorylated form (16). Hence, we examined the effect of siRNA-mediated depletion of IRGM on HCV-triggered phosphorylation of GBF1T1337 and AMPKαT172, phosphorylation events that mediate the activation of AMPK and GBF1.…”

Section: Resultsmentioning

confidence: 96%

“…Human IRGM regulates autophagy (16) and has been identified as a risk factor for Crohn's disease and tuberculosis risk.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, IRGM was found to regulate ULK1 and to promote the formation of autophagy initiation complexes (16). Hence, IRGM contributes to autophagy, but the mechanisms by which IRGM participates during viral infections are unknown.…”

Section: Significancementioning

confidence: 99%

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Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Hansen

Johnsen

Stiberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

115

127

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Positive-stranded RNA viruses, such as hepatitis C virus (HCV), assemble their viral replication complexes by remodeling host intracellular membranes to a membranous web. The precise composition of these replication complexes and the detailed mechanisms by which they are formed are incompletely understood. Here we show that the human immunity-related GTPase M (IRGM), known to contribute to autophagy, plays a previously unrecognized role in this process. We show that IRGM is localized at the Golgi apparatus and regulates the fragmentation of Golgi membranes in response to HCV infection, leading to colocalization of Golgi vesicles with replicating HCV. Our results show that IRGM controls phosphorylation of GBF1, a guanine nucleotide exchange factor for Arf-GTPases, which normally operates in Golgi membrane dynamics and vesicle coating in resting cells. We also find that HCV triggers IRGM-mediated phosphorylation of the early autophagy initiator ULK1, thereby providing mechanistic insight into the role of IRGM in HCV-mediated autophagy. Collectively, our results identify IRGM as a key Golgi-situated regulator that links intracellular membrane remodeling by autophagy and Golgi fragmentation with viral replication.HCV | Golgi fragmentation | autophagy | IRGM | membranous web H epatitis C virus (HCV) is a positive-sense RNA virus in the family Flaviviridae that is a major cause of chronic liver disease. All positive-strand RNA viruses studied until now, including HCV, replicate their genomes in association with cellular membrane rearrangements. In this process, viruses remodel intracellular membranes [e.g., of mitochondria, endoplasmic reticulum (ER), and plasma membrane] to generate membrane structures such as single-or double-membrane vesicles that contribute to viral replication complexes (VRCs). HCV replication takes place at a unique subcellular compartment, the membranous web (MW), which has been proposed to be derived from the ER (1, 2). The HCV MW has a complex morphology consisting of clusters of single-, double-, and multimembrane vesicles and probably includes autophagosomes and lipid droplets (1, 3, 4). Recent findings reveal that the MW is produced by distinct HCV nonstructural (NS) proteins acting through sequential interaction with several host factors, such as the virus-targeted phosphatidylinositol-4 kinase III α (PI4KIIIα) (2, 3), but the full spectrum of host components and precise membrane composition that supports HCV replication are not fully defined.Autophagy is an evolutionarily conserved cellular mechanism that involves intracellular membrane trafficking and degradation to maintain cell homeostasis. Viruses, including HCV, have been reported to exploit autophagy for replication purposes (4-6), but the mechanism by which this exploitation occurs is largely unknown. De novo synthesis of autophagosomes is a complex process that involves the formation of a phagophore membrane and its elongation. Initiation of autophagy is regulated by the mammalian target of rapamycin complex 1 (mTORC1), which neg...

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Section: Resultsmentioning

confidence: 96%

“…Human IRGM regulates autophagy (16) and has been identified as a risk factor for Crohn's disease and tuberculosis risk.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Hansen

Johnsen

Stiberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

115

127

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

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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“…NOD2 enhances K63-linked ubiquitination of IRGM, enabling IRGM to interact with ULK1 and Beclin 1 (13). IRGM also stimulates autophagy by activating AMPK (13).…”

mentioning

confidence: 99%

Identification of Signaling Pathways by Which CD40 Stimulates Autophagy and Antimicrobial Activity against Toxoplasma gondii in Macrophages

et al. 2016

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CD40 is an important stimulator of autophagy and autophagic killing of Toxoplasma gondii in host cells. In contrast to autophagy induced by nutrient deprivation or pattern recognition receptors, less is known about the effects of cell-mediated immunity on Beclin 1 and ULK1, key regulators of autophagy. Here we studied the molecular mechanisms by which CD40 stimulates autophagy in macrophages. CD40 ligation caused biphasic Jun N-terminal protein kinase (JNK) phosphorylation. The second phase of JNK phosphorylation was dependent on autocrine production of tumor necrosis factor alpha (TNF-␣). TNF-␣ and JNK signaling were required for the CD40-induced increase in autophagy. JNK signaling downstream of CD40 caused Ser-87 phosphorylation of Bcl-2 and dissociation between Bcl-2 and Beclin 1, an event known to stimulate the autophagic function of Beclin 1. However, TNF-␣ alone was unable to stimulate autophagy. CD40 also stimulated autophagy via a pathway that included calcium/calmodulin-dependent kinase kinase ␤ (CaMKK␤), AMP-activated protein kinase (AMPK), and ULK1. CD40 caused AMPK phosphorylation at its activating site, Thr-172. This effect was mediated by CaMKK␤ and was not impaired by neutralization of TNF-␣. CD40 triggered AMPK-dependent Ser-555 phosphorylation of ULK1. CaMKK␤, AMPK, and ULK1 were required for CD40-induced increase in autophagy. CD40-mediated autophagic killing of Toxoplasma gondii is known to require TNF-␣. Knockdown of JNK, CaMKK␤, AMPK, or ULK1 prevented T. gondii killing in CD40-activated macrophages. The second phase of JNK phosphorylation-Bcl-2 phosphorylation-Bcl-2-Beclin 1 dissociation and AMPK phosphorylation-ULK1 phosphorylation occurred simultaneously at ϳ4 h post-CD40 stimulation. Thus, CaMKK␤ and TNF-␣ are upstream molecules by which CD40 acts on ULK1 and Beclin 1 to stimulate autophagy and killing of T. gondii.

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IRGM Governs the Core Autophagy Machinery to Conduct Antimicrobial Defense

Cited by 201 publications

References 48 publications

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

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

Identification of Signaling Pathways by Which CD40 Stimulates Autophagy and Antimicrobial Activity against Toxoplasma gondii in Macrophages

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