Autophagy gene-dependent intracellular immunity triggered by interferon-γ

Abstract

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 <i>Wipi2</i>, <i>Atg9</i>, and <i>Gate-16</i>, as well as ubiquitin ligase complex genes <i>Cul3</i> and <i>Klhl9</i> are required for IFNγ-induced inhibition of murine norovirus (norovirus hereinafter) replication in mouse cells. <i>WIPI2</i> and <i>GATE-16</i> were also required for IFNγ-mediated restriction of parasite growth within the <i>Toxoplasma gondii</i> 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.