Autophagy gene-dependent intracellular immunity triggered by interferon-γ

Michael R. McAllaster, Jaya Bhushan, Dale R. Balce, Anthony Orvedahl, Arnold Park, Seungmin Hwang, Meagan E. Sullender, L. David Sibley, Herbert W. Virgin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Genes 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.

Original languageEnglish
JournalmBio
Volume14
Issue number6
DOIs
StatePublished - Dec 2023

Keywords

  • Toxoplasmsa gondii
  • UFMylation
  • autophagy
  • interferons
  • norovirus

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