Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct cellular processes with significant physiologic importance. One of the first-described of these ATG gene-dependent 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 new genes that are required for or that negatively regulate this immune mechanism. Enzymes involved in the conjugation of UFM1 to target proteins including UFC1 and UBA5, negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. IFNγ-induced inhibition of norovirus replication required Wipi2b and Atg9a, but not Becn1 (encoding Beclin1), Atg14, or Sqstm1. The phosphatidylinositol-3-phosphate and ATG16L1 binding domains of WIPI2B were required for IFNγ-induced inhibition of norovirus replication. Both WIPI2 and SQSTM1 were required for IFN?-induced inhibition of Toxoplasma gondii replication in HeLa cells. These studies further delineate the mechanisms of a programmable form of cytokine-induced intracellular immunity that relies on an expanding cassette of essential ATG genes to restrict the growth of phylogenetically diverse pathogens.

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