Essential Role of mGBP7 for Survival of Toxoplasma gondii Infection

ABSTRACT Members of the murine guanylate-binding protein family (mGBP) are induced by interferon gamma (IFN-γ) and have been shown to be important factors in cell-autonomous immunity toward the intracellular pathogen Toxoplasma gondii. Previously, we identified that mGBP2 mediates disruption of the parasitophorous vacuole membrane (PVM) and directly assaults the plasma membrane of the parasite. Here, we show that mGBP7-deficient mice are highly susceptible to T. gondii infection. This is demonstrated by the loss of parasite replication control, pronounced development of ascites, and death of the animals in the acute infection phase. Interestingly, live-cell microscopy revealed that mGBP7 recruitment to the PVM occurs after mGBP2 recruitment, followed by disruption of the PVM and T. gondii integrity and accumulation of mGBP7 inside the parasite. This study defines mGBP7 as a crucial effector protein in resistance to intracellular T. gondii. IMPORTANCE Guanylate-binding proteins (GBPs) are induced by the inflammatory cytokine interferon gamma (IFN-γ) and have been shown to be important factors in the defense of the intracellular pathogen Toxoplasma gondii. In previous studies, we showed that members of the mouse GBP family, such as mGBP2 and mGBP7, accumulate at the parasitophorous vacuole of T. gondii, which is the replicatory niche of the parasite. In this study, we show that mice deficient in mGBP7 succumb early after infection with T. gondii, showing a complete failure of resistance to the pathogen. On a molecular level, mGBP7 is found directly at the parasite, likely mediating its destruction.

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Interleukin-17A-Deficient Mice Are Highly Susceptible to Toxoplasma gondii Infection Due to Excessively Induced T. gondii HSP70 and Interferon Gamma Production

Infection and Immunity ◽

10.1128/iai.00399-17 ◽

2017 ◽

Vol 85 (12) ◽

Cited By ~ 12

Author(s):

Masataka Moroda ◽

Masaya Takamoto ◽

Yoichiro Iwakura ◽

Jun Nakayama ◽

Fumie Aosai

Keyword(s):

Toxoplasma Gondii ◽

Interferon Gamma ◽

Acute Phase ◽

Host Defense ◽

Hsp70 Expression ◽

Mesenteric Lymph Nodes ◽

Content Type ◽

Ifn Γ ◽

Toxoplasma Gondii Infection ◽

Deficient Mice

ABSTRACT Interleukin17A (IL-17A) is known to be involved in the host defense against pathogens and the pathogenesis of autoimmune diseases. Previously, we showed that excessive amounts of interferon gamma (IFN-γ) play an important role in the pathogenesis of the lethal effects of Toxoplasma gondii by inducing anaphylactic responses. In the study described in this report, we examined the effects of IL-17A deficiency on murine host defense against oral T. gondii infection. IL-17A-deficient C57BL/6 (B6) mice exhibited higher rates of mortality than wild-type (WT) mice during the acute phase of T. gondii infection. CD4+ T cells in the mesenteric lymph nodes (mLNs) and ileum of T. gondii-infected IL-17A-deficient mice produced higher levels of IFN-γ than did those of WT mice. In addition, the level of T. gondii HSP70 (T.g.HSP70) expression was also significantly increased in the ileum, mLNs, liver, and spleen of infected IL-17A-deficient mice compared with that in WT mice. These elevated levels of expression of T.g.HSP70 and IFN-γ in infected IL-17A-deficient mice were presumably linked to the IL-17A defect since they decreased to WT levels after treatment with recombinant IL-17A. Furthermore, IL-17A-deficient mice were highly susceptible to the anaphylactic effect of T.g.HSP70, and the survival of IL-17A-deficient mice during the acute phase was improved by treatment with an anti-T.g.HSP70 monoclonal antibody. These results suggest that IL-17A plays an important role in host survival against T. gondii infection by protecting the host from an anaphylactic reaction via the downregulation of T.g.HSP70 and IFN-γ production.

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Immediate Interferon Gamma Induction Determines Murine Host Compatibility Differences between Toxoplasma gondii and Neospora caninum

Infection and Immunity ◽

10.1128/iai.00027-20 ◽

2020 ◽

Vol 88 (4) ◽

Cited By ~ 1

Author(s):

Rachel S. Coombs ◽

Matthew L. Blank ◽

Elizabeth D. English ◽

Yaw Adomako-Ankomah ◽

Ifeanyi-Chukwu Samuel Urama ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Interferon Gamma ◽

Neospora Caninum ◽

Ectopic Expression ◽

Parasite Burden ◽

Interleukin 12 ◽

Content Type ◽

Ifn Γ ◽

And Control

ABSTRACT Rodents are critical for the transmission of Toxoplasma gondii to the definitive feline host via predation, and this relationship has been extensively studied as a model for immune responses to parasites. Neospora caninum is a closely related coccidian parasite of ruminants and canines but is not naturally transmitted by rodents. We compared mouse innate immune responses to N. caninum and T. gondii and found marked differences in cytokine levels and parasite growth kinetics during the first 24 h postinfection (hpi). N. caninum-infected mice produced significantly higher levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) by as early as 4 hpi, but the level of IFN-γ was significantly lower or undetectable in T. gondii-infected mice during the first 24 hpi. “Immediate” IFN-γ and IL-12p40 production was not detected in MyD88−/− mice. However, unlike IL-12p40−/− and IFN-γ−/− mice, MyD88−/− mice survived N. caninum infections at the dose used in this study. Serial measures of parasite burden showed that MyD88−/− mice were more susceptible to N. caninum infections than wild-type (WT) mice, and control of parasite burdens correlated with a pulse of serum IFN-γ at 3 to 4 days postinfection in the absence of detectable IL-12. Immediate IFN-γ was partially dependent on the T. gondii mouse profilin receptor Toll-like receptor 11 (TLR11), but the ectopic expression of N. caninum profilin in T. gondii had no impact on early IFN-γ production or parasite proliferation. Our data indicate that T. gondii is capable of evading host detection during the first hours after infection, while N. caninum is not, and this is likely due to the early MyD88-dependent recognition of ligands other than profilin.

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Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0353-9 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Miwa Sasai ◽

Masahiro Yamamoto

Keyword(s):

Immune Response ◽

Toxoplasma Gondii ◽

Immune Responses ◽

Parasitophorous Vacuole ◽

Interferon Γ ◽

Protective Role ◽

Ifn Γ ◽

Acquired Immune Responses ◽

Toxoplasma Gondii Infection ◽

Antimicrobial Immunity

AbstractHosts have been fighting pathogens throughout the evolution of all infectious diseases. Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals. Similar to antimicrobial immunity against other organisms, the immune response against T. gondii activates innate immunity and in turn induces acquired immune responses. After activation of acquired immunity, host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases. IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes. Recent studies suggest that the cell-autonomous immune response plays a protective role in host defense against not only T. gondii but also various intracellular bacteria. Moreover, the negative regulatory mechanisms of such strong immune responses are also important for host survival after infection. In this review, we will discuss in detail recent advances in the understanding of host defenses against T. gondii and the roles played by cell-autonomous immune responses.

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STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection

Infection and Immunity ◽

10.1128/iai.72.3.1257-1264.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1257-1264 ◽

Cited By ~ 79

Author(s):

L. Cristina Gavrilescu ◽

Barbara A. Butcher ◽

Laura Del Rio ◽

Gregory A. Taylor ◽

Eric Y. Denkers

Keyword(s):

T Cell ◽

Toxoplasma Gondii ◽

Intracellular Signaling ◽

Acute Infection ◽

Gamma Interferon ◽

Interleukin 12 ◽

Ifn Γ ◽

Toxoplasma Gondii Infection ◽

Oxide Synthase

ABSTRACT The opportunistic protozoan Toxoplasma gondii is a prototypic Th1-inducing pathogen inducing strong gamma interferon (IFN-γ) cytokine responses that are required to survive infection. Intracellular signaling intermediate STAT1 mediates many effects of IFN-γ and is implicated in activation of T-bet, a master regulator of Th1 differentiation. Here, we show that T. gondii-infected STAT1-null mice fail to upregulate the IFN-γ-dependent effector molecules inducible nitric oxide synthase (iNOS), IGTP, and LRG-47, which are required for mice to survive infection. Both T-bet and interleukin-12 receptor β2 (IL-12Rβ2) failed to undergo normal upregulation in response to T. gondii. Development of IFN-γ-producing CD4+ and CD8+ T lymphocytes was severely curtailed in the absence of STAT1, but a substantial level of STAT1-independent non-T-cell-derived IFN-γ was induced. Absence of STAT1 also resulted in increased IL-4, Arg1, Ym1, and Fizz1, markers of Th2 differentiation and alternative macrophage activation. Together, the results show that T. gondii induces STAT1-dependent T-lymphocyte and STAT1-independent non-T-cell IFN-γ production, but that effector functions of this type 1 cytokine cannot operate in the absence of STAT1, resulting in extreme susceptibility to acute infection.

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Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses

Journal of Experimental Medicine ◽

10.1084/jem.20160340 ◽

2016 ◽

Vol 213 (9) ◽

pp. 1779-1798 ◽

Cited By ~ 87

Author(s):

Gabrielle Gay ◽

Laurence Braun ◽

Marie-Pierre Brenier-Pinchart ◽

Julien Vollaire ◽

Véronique Josserand ◽

...

Keyword(s):

Gene Expression ◽

Toxoplasma Gondii ◽

Acute Infection ◽

Protective Role ◽

Immune Gene ◽

Nucleosome Remodeling ◽

Inflammatory Monocytes ◽

Ifn Γ ◽

Immune Pathology ◽

Toxoplasma Gondii Infection

An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii–targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ–stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1+ inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ–mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism.

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CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection

Infection and Immunity ◽

10.1128/iai.02536-14 ◽

2014 ◽

Vol 83 (2) ◽

pp. 721-729 ◽

Cited By ~ 16

Author(s):

Deeqa A. Mahamed ◽

Leon E. Toussaint ◽

Margaret S. Bynoe

Keyword(s):

Toxoplasma Gondii ◽

Adenosine Receptor ◽

Oral Infection ◽

Intracellular Pathogen ◽

Necrosis Factor Alpha ◽

Extracellular Adenosine ◽

Content Type ◽

Adenosine Receptor Agonist ◽

Obligate Intracellular Pathogen ◽

Toxoplasma Gondii Infection

As an obligate intracellular pathogen, the apicomplexan parasiteToxoplasma gondiievades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ectoenzyme CD73, which generates adenosine in the extracellular matrix, were resistant to chronic toxoplasmosis after oral infection withT. gondii. Resistance in CD73 knockout mice was due to a delay in parasite differentiation in the central nervous system (CNS). To further clarify the role of CD73 and extracellular adenosine inT. gondiipathogenesis, we infected wild-type (WT) and CD73−/−mice withT. gondiicysts systemically by the intraperitoneal (i.p.) route. In contrast to oral infection, i.p. infected CD73−/−mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. Administration of the broad-spectrum adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) protected CD73−/−mice againstT. gondii-induced immunopathology, suggesting that the absence of CD73-generated adenosine led to the increased susceptibility in these mice. Peritoneal exudate cells from infected CD73−/−mice produced higher levels of the inflammatory mediators nitric oxide, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression in both hematopoietic and nonhematopoietic compartments contributes to limitingT. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A2Awere more susceptible to immunopathology during intraperitoneal infection withT. gondiithan WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage due to an intracellular pathogen and promotes host survival.

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A Glycosylphosphatidylinositol-Anchored Carbonic Anhydrase-Related Protein of Toxoplasma gondii Is Important for Rhoptry Biogenesis and Virulence

mSphere ◽

10.1128/msphere.00027-17 ◽

2017 ◽

Vol 2 (3) ◽

Cited By ~ 13

Author(s):

Nathan M. Chasen ◽

Beejan Asady ◽

Leandro Lemgruber ◽

Rossiane C. Vommaro ◽

Jessica C. Kissinger ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Carbonic Anhydrase ◽

Host Cell ◽

Parasitophorous Vacuole ◽

Lytic Cycle ◽

Host Cells ◽

Intracellular Pathogen ◽

Related Protein ◽

Content Type ◽

Initial Interaction

ABSTRACT Toxoplasma gondii is an intracellular pathogen that infects humans and animals. The pathogenesis of T. gondii is linked to its lytic cycle, which starts when tachyzoites invade host cells and secrete proteins from specialized organelles. Once inside the host cell, the parasite creates a parasitophorous vacuole (PV) where it divides. Rhoptries are specialized secretory organelles that contain proteins, many of which are secreted during invasion. These proteins have important roles not only during the initial interaction between parasite and host but also in the formation of the PV and in the modification of the host cell. We report here the identification of a new T. gondii carbonic anhydrase-related protein (TgCA_RP), which localizes to rhoptries of mature tachyzoites. TgCA_RP is important for the morphology of rhoptries and for invasion and growth of parasites. TgCA_RP is also critical for parasite virulence. We propose that TgCA_RP plays a role in the biogenesis of rhoptries. Carbonic anhydrase-related proteins (CARPs) have previously been described as catalytically inactive proteins closely related to α-carbonic anhydrases (α-CAs). These CARPs are found in animals (both vertebrates and invertebrates) and viruses as either independent proteins or domains of other proteins. We report here the identification of a new CARP (TgCA_RP) in the unicellular organism Toxoplasma gondii that is related to the recently described η-class CA found in Plasmodium falciparum. TgCA_RP is posttranslationally modified at its C terminus with a glycosylphosphatidylinositol anchor that is important for its localization in intracellular tachyzoites. The protein localizes throughout the rhoptry bulbs of mature tachyzoites and to the outer membrane of nascent rhoptries in dividing tachyzoites, as demonstrated by immunofluorescence and immunoelectron microscopy using specific antibodies. T. gondii mutant tachyzoites lacking TgCA_RP display a growth and invasion phenotype in vitro and have atypical rhoptry morphology. The mutants also exhibit reduced virulence in a mouse model. Our results show that TgCA_RP plays an important role in the biogenesis of rhoptries. IMPORTANCE Toxoplasma gondii is an intracellular pathogen that infects humans and animals. The pathogenesis of T. gondii is linked to its lytic cycle, which starts when tachyzoites invade host cells and secrete proteins from specialized organelles. Once inside the host cell, the parasite creates a parasitophorous vacuole (PV) where it divides. Rhoptries are specialized secretory organelles that contain proteins, many of which are secreted during invasion. These proteins have important roles not only during the initial interaction between parasite and host but also in the formation of the PV and in the modification of the host cell. We report here the identification of a new T. gondii carbonic anhydrase-related protein (TgCA_RP), which localizes to rhoptries of mature tachyzoites. TgCA_RP is important for the morphology of rhoptries and for invasion and growth of parasites. TgCA_RP is also critical for parasite virulence. We propose that TgCA_RP plays a role in the biogenesis of rhoptries.

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Involvement of Host Defense Mechanisms against Toxoplasma gondii Infection in Anhedonic and Despair-Like Behaviors in Mice

Infection and Immunity ◽

10.1128/iai.00007-17 ◽

2017 ◽

Vol 85 (4) ◽

Cited By ~ 11

Author(s):

Motamed Elsayed Mahmoud ◽

Ragab Fereig ◽

Yoshifumi Nishikawa

Keyword(s):

Toxoplasma Gondii ◽

Host Defense ◽

Defense Mechanisms ◽

Defense Mechanism ◽

Acute Infection ◽

Sickness Behavior ◽

Wild Type ◽

Chronic Infections ◽

Content Type ◽

Ifn Γ

ABSTRACT Toxoplasma gondii is a pathogen relevant to psychiatric disorders. We recently showed that reactivation of chronic T. gondii infection induced depression-like behaviors in mice. Furthermore, it has been hypothesized that depression-like behaviors are mediated via a host defense mechanism against invading pathogens; proximate mechanisms of this behavioral hypothesis remain unclear. In the present study, we investigate the contribution of indoleamine 2,3-dioxygenase (IDO), inflammation, and interferon gamma (IFN-γ) to anhedonic and despair-related behaviors in T. gondii-infected mice by using sucrose preference and forced-swim tests, respectively. First, we confirmed that BALB/c mice exhibited both sickness and depression-like behaviors during acute infection. Treatment of infected wild-type mice with minocycline (anti-inflammatory drug) abated sickness and anhedonic and despair-like behaviors, whereas in T. gondii-infected mice, treatment normalized kynurenine/tryptophan (Kyn/Trp) ratios in both plasma and brain tissue. Additionally, T. gondii infection failed to induce anhedonic and despair-like behaviors or increase the Kyn/Trp ratio in immunocompromised (IFN-γ−/−) mice, whereas sickness behavior was observed in both immunocompetent and IFN-γ−/− mice following infection. Furthermore, treatment with 1-methyl tryptophan (an IDO inhibitor) did not affect locomotor activity, attenuated clinical scores and anhedonic and despair-like behaviors, and resulted in normal Kyn/Trp ratios in T. gondii-infected wild-type mice. Although low levels of serotonin and dopamine were observed in the brain during acute and chronic infections, anhedonic and despair-like behaviors were not detected in the chronic stage of infection. Collectively, our results demonstrated that immune enhancement in response to infection with T. gondii resulted in IFN-γ production, IDO activation, and inflammation associated with anhedonic and despair-like behaviors.

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Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication

Infection and Immunity ◽

10.1128/iai.00416-13 ◽

2013 ◽

Vol 81 (12) ◽

pp. 4341-4349 ◽

Cited By ~ 46

Author(s):

Wendy Niedelman ◽

Joris K. Sprokholt ◽

Barbara Clough ◽

Eva-Maria Frickel ◽

Jeroen P. J. Saeij

Keyword(s):

Cell Death ◽

Toxoplasma Gondii ◽

Human Fibroblasts ◽

Protozoan Parasite ◽

Resistance Mechanisms ◽

Gamma Interferon ◽

Content Type ◽

Food Borne Illness ◽

Ifn Γ ◽

Toxoplasma Gondii Infection

ABSTRACTThe intracellular protozoan parasiteToxoplasma gondiiis a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance toToxoplasmais dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate immunity in nonhematopoietic cells has been extensively studied in mice, it remains unclear what resistance mechanisms are relied on in nonhematopoietic human cells. Here, we report an IFN-γ-induced mechanism of resistance toToxoplasmain primary human foreskin fibroblasts (HFFs) that does not depend on the deprivation of tryptophan or iron. In addition, infection is still controlled in HFFs deficient in the p65 guanylate binding proteins GBP1 or GBP2 and the autophagic protein ATG5. Resistance is coincident with host cell death that is not dependent on the necroptosis mediator RIPK3 or caspases and is correlated with early egress of the parasite before replication. This IFN-γ-induced cell death and early egress limits replication in HFFs and could promote clearance of the parasite by immune cells.

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ISG15 Connects Autophagy and IFN-γ-Dependent Control of Toxoplasma gondii Infection in Human Cells

mBio ◽

10.1128/mbio.00852-20 ◽

2020 ◽

Vol 11 (5) ◽

Author(s):

Jaya Bhushan ◽

Joshua B. Radke ◽

Yi-Chieh Perng ◽

Michael Mcallaster ◽

Deborah J. Lenschow ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Parasitophorous Vacuole ◽

Interferon Γ ◽

Parasite Growth ◽

Human Cells ◽

Growth Restriction ◽

Intracellular Pathogens ◽

Functional Link ◽

Content Type ◽

Ifn Γ

ABSTRACT The intracellular protozoan parasite Toxoplasma gondii is capable of infecting most nucleated cells, where it survives in a specially modified compartment called the parasitophorous vacuole (PV). Interferon gamma (IFN-γ) is the major cytokine involved in activating cell-autonomous immune responses to inhibit parasite growth within this intracellular niche. In HeLa cells, IFN-γ treatment leads to ubiquitination of susceptible parasite strains, recruitment of the adaptors p62 and NDP52, and engulfment in microtubule-associated protein 1 light chain 3 (LC3)-positive membranes that restrict parasite growth. IFN-γ-mediated growth restriction depends on core members of the autophagy (ATG) pathway but not the initiation or degradative steps in the process. To explore the connection between these different pathways, we used permissive biotin ligation to identify proteins that interact with ATG5 in an IFN-γ-dependent fashion. Network analysis of the ATG5 interactome identified interferon-stimulated gene 15 (ISG15), which is highly upregulated by IFN treatment, as a hub connecting the ATG complex with other IFN-γ-induced genes, suggesting that it forms a functional link between the pathways. Deletion of ISG15 resulted in impaired recruitment of p62, NDP52, and LC3 to the PV and loss of IFN-γ-restricted parasite growth. The function of ISG15 required conjugation, and a number of ISGylated targets overlapped with the IFN-γ-dependent ATG5 interactome, including the adapter p62. Collectively, our findings establish a role for ISG15 in connecting the ATG pathway with IFN-γ-dependent restriction of T. gondii in human cells. IMPORTANCE Interferon(s) provide the primary defense against intracellular pathogens, a property ascribed to their ability to upregulate interferon-stimulated genes. Due to the sequestered niche occupied by Toxoplasma gondii, the host has elaborated intricate ways to target the parasite within its vacuole. One such mechanism is the recognition by a noncanonical autophagy pathway that envelops the parasite-containing vacuole and stunts growth in human cells. Remarkably, autophagy-dependent growth restriction requires interferon-γ, yet none of the classical components of autophagy are induced by interferon. Our studies draw a connection between these pathways by demonstrating that the antiviral protein ISG15, which is normally upregulated by interferons, links the autophagy-mediated control to ubiquitination of the vacuole. These findings suggest a similar link between interferon-γ signaling and autophagy that may underlie defense against other intracellular pathogens.

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