Autophagy gene-dependent intracellular immunity triggered by interferon-γ

• Published in: mBio Vol. 14; no. 6; p. e0233223
• Main Authors: McAllaster, Michael R, Bhushan, Jaya, Balce, Dale R, Orvedahl, Anthony, Park, Arnold, Hwang, Seungmin, Sullender, Meagan E, Sibley, L David, Virgin, Herbert W
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 19.12.2023
• Subjects: autophagy; Host-Microbial Interactions; interferons; norovirus; Research Article; Toxoplasmsa gondii; UFMylation; UFMylation; Toxoplasmsa gondii; autophagy; interferons; norovirus
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.02332-23

Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct and physiologically important cellular processes. Some functions of genes are independent of their role in degradative autophagy. One of the first described of these gene-dependent, but degradative autophagy independent, processes is the requirement for a subset of genes in interferon-γ (IFNγ)-induced inhibition of norovirus and 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 . IFNγ-induced inhibition of norovirus replication required (also termed ), , , , and but not (encoding Beclin 1), , , or . 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 , , and 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 infection in human cells. These studies further delineate the genes and mechanisms of an gene-dependent programmable form of cytokine-induced innate intracellular immunity. IMPORTANCE Interferon-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 , , and , as well as ubiquitin ligase complex genes and are required for IFNγ-induced inhibition of murine norovirus (norovirus hereinafter) replication in mouse cells. and were also required for IFNγ-mediated restriction of parasite growth within the 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.