Autophagy gene-dependent intracellular immunity triggered by interferon-γ
ABSTRACTGenes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct and physiologically important cellular processes. Some functions of ATG genes are independent of their role in degradative autophagy. One of the first described of these ATG gene-depend...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-12-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02332-23 |
| _version_ | 1797378916717953024 |
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| author | Michael R. McAllaster Jaya Bhushan Dale R. Balce Anthony Orvedahl Arnold Park Seungmin Hwang Meagan E. Sullender L. David Sibley Herbert W. Virgin |
| author_facet | Michael R. McAllaster Jaya Bhushan Dale R. Balce Anthony Orvedahl Arnold Park Seungmin Hwang Meagan E. Sullender L. David Sibley Herbert W. Virgin |
| author_sort | Michael R. McAllaster |
| collection | DOAJ |
| description | ABSTRACTGenes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct and physiologically important cellular processes. Some functions of ATG genes are independent of their role in degradative autophagy. One of the first described of these ATG gene-dependent, but degradative autophagy independent, processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of norovirus and Toxoplasma gondii replication. Herein, we identified additional genes that are required for, or that negatively regulate, this innate immune effector pathway. Enzymes in the UFMylation pathway negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. IFNγ-induced inhibition of norovirus replication required Gate-16 (also termed GabarapL2), Wipi2b, Atg9a, Cul3, and Klhl9 but not Becn1 (encoding Beclin 1), Atg14, Uvrag, or Sqstm1. The phosphatidylinositol-3-phosphate and ATG16L1-binding domains of WIPI2B, as well as the ATG5-binding domain of ATG16L1, were required for IFNγ-induced inhibition of norovirus replication. Other members of the Cul3, Atg8, and Wipi2 gene families were not required, demonstrating exquisite specificity within these gene families for participation in IFNγ action. The generality of some aspects of this mechanism was demonstrated by a role for GATE-16 and WIPI2 in IFNγ-induced control of Toxoplasma gondii infection in human cells. These studies further delineate the genes and mechanisms of an ATG gene-dependent programmable form of cytokine-induced innate intracellular immunity.IMPORTANCEInterferon-γ (IFNγ) is a critical mediator of cell-intrinsic immunity to intracellular pathogens. Understanding the complex cellular mechanisms supporting robust interferon-γ-induced host defenses could aid in developing new therapeutics to treat infections. Here, we examined the impact of autophagy genes in the interferon-γ-induced host response. We demonstrate that genes within the autophagy pathway including Wipi2, Atg9, and Gate-16, as well as ubiquitin ligase complex genes Cul3 and Klhl9 are required for IFNγ-induced inhibition of murine norovirus (norovirus hereinafter) replication in mouse cells. WIPI2 and GATE-16 were also required for IFNγ-mediated restriction of parasite growth within the Toxoplasma gondii parasitophorous vacuole in human cells. Furthermore, we found that perturbation of UFMylation pathway components led to more robust IFNγ-induced inhibition of norovirus via regulation of endoplasmic reticulum (ER) stress. Enhancing or inhibiting these dynamic cellular components could serve as a strategy to control intracellular pathogens and maintain an effective immune response. |
| first_indexed | 2024-03-08T20:14:32Z |
| format | Article |
| id | doaj.art-ee73c35548d94fc394c27a7238cc9bbd |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-08T20:14:32Z |
| publishDate | 2023-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-ee73c35548d94fc394c27a7238cc9bbd2023-12-22T19:53:44ZengAmerican Society for MicrobiologymBio2150-75112023-12-0114610.1128/mbio.02332-23Autophagy gene-dependent intracellular immunity triggered by interferon-γMichael R. McAllaster0Jaya Bhushan1Dale R. Balce2Anthony Orvedahl3Arnold Park4Seungmin Hwang5Meagan E. Sullender6L. David Sibley7Herbert W. Virgin8Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USAVir Biotechnology, San Francisco, California, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USAVir Biotechnology, San Francisco, California, USAVir Biotechnology, San Francisco, California, USADivision of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USAABSTRACTGenes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct and physiologically important cellular processes. Some functions of ATG genes are independent of their role in degradative autophagy. One of the first described of these ATG gene-dependent, but degradative autophagy independent, processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of norovirus and Toxoplasma gondii replication. Herein, we identified additional genes that are required for, or that negatively regulate, this innate immune effector pathway. Enzymes in the UFMylation pathway negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. IFNγ-induced inhibition of norovirus replication required Gate-16 (also termed GabarapL2), Wipi2b, Atg9a, Cul3, and Klhl9 but not Becn1 (encoding Beclin 1), Atg14, Uvrag, or Sqstm1. The phosphatidylinositol-3-phosphate and ATG16L1-binding domains of WIPI2B, as well as the ATG5-binding domain of ATG16L1, were required for IFNγ-induced inhibition of norovirus replication. Other members of the Cul3, Atg8, and Wipi2 gene families were not required, demonstrating exquisite specificity within these gene families for participation in IFNγ action. The generality of some aspects of this mechanism was demonstrated by a role for GATE-16 and WIPI2 in IFNγ-induced control of Toxoplasma gondii infection in human cells. These studies further delineate the genes and mechanisms of an ATG gene-dependent programmable form of cytokine-induced innate intracellular immunity.IMPORTANCEInterferon-γ (IFNγ) is a critical mediator of cell-intrinsic immunity to intracellular pathogens. Understanding the complex cellular mechanisms supporting robust interferon-γ-induced host defenses could aid in developing new therapeutics to treat infections. Here, we examined the impact of autophagy genes in the interferon-γ-induced host response. We demonstrate that genes within the autophagy pathway including Wipi2, Atg9, and Gate-16, as well as ubiquitin ligase complex genes Cul3 and Klhl9 are required for IFNγ-induced inhibition of murine norovirus (norovirus hereinafter) replication in mouse cells. WIPI2 and GATE-16 were also required for IFNγ-mediated restriction of parasite growth within the Toxoplasma gondii parasitophorous vacuole in human cells. Furthermore, we found that perturbation of UFMylation pathway components led to more robust IFNγ-induced inhibition of norovirus via regulation of endoplasmic reticulum (ER) stress. Enhancing or inhibiting these dynamic cellular components could serve as a strategy to control intracellular pathogens and maintain an effective immune response.https://journals.asm.org/doi/10.1128/mbio.02332-23interferonsToxoplasmsa gondiiautophagyUFMylationnorovirus |
| spellingShingle | Michael R. McAllaster Jaya Bhushan Dale R. Balce Anthony Orvedahl Arnold Park Seungmin Hwang Meagan E. Sullender L. David Sibley Herbert W. Virgin Autophagy gene-dependent intracellular immunity triggered by interferon-γ mBio interferons Toxoplasmsa gondii autophagy UFMylation norovirus |
| title | Autophagy gene-dependent intracellular immunity triggered by interferon-γ |
| title_full | Autophagy gene-dependent intracellular immunity triggered by interferon-γ |
| title_fullStr | Autophagy gene-dependent intracellular immunity triggered by interferon-γ |
| title_full_unstemmed | Autophagy gene-dependent intracellular immunity triggered by interferon-γ |
| title_short | Autophagy gene-dependent intracellular immunity triggered by interferon-γ |
| title_sort | autophagy gene dependent intracellular immunity triggered by interferon γ |
| topic | interferons Toxoplasmsa gondii autophagy UFMylation norovirus |
| url | https://journals.asm.org/doi/10.1128/mbio.02332-23 |
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