Antiviral defense in aged Caenorhabditis elegans declines due to loss of DRH-1/RIG-I deSUMOylation via ULP-4/SENP7

Abstract

Innate host defense mechanisms require posttranslational modifications (PTM) to protect against viral infection. Age-associated immunosenescence results in increased pathogenesis and mortality in the elderly, but the contribution of altered PTM regulation to immunosenescence is unknown. SUMOylation is a rapid and reversible post-translational modification that has been implicated in age-associated disease and plays conflicting roles in viral replication and antiviral defenses in mammals. We have discovered in Caenorhabditis elegans that induction of antiviral defense is regulated through SUMOylation of DRH-1, the ortholog of the DEAD/H-box helicase and cytosolic pattern recognition receptor RIG-I, and that this regulation breaks down during aging. We find the SUMO isopeptidase ULP-4 is essential for deSUMOylation of DRH-1 and activation of the intracellular pathogen response (IPR) after exposure to Orsay virus (OV), a natural enteric C. elegans pathogen. ULP-4 promotes stabilization of DRH-1, which translocates to the mitochondria to activate the IPR in young animals exposed to virus. Loss of either drh-1 or ulp-4 compromises antiviral defense resulting in a failure to clear the virus and signs of intestinal pathogenesis. During aging, expression of ulp-4 decreases, which results in increased proteosomal degradation of DRH-1 and loss of the IPR. Mutating the DRH-1 SUMOylated lysines resulted in the constitutive activation of the IPR in young animals and partially rescued the age-associated lost inducibility of the IPR. Our work establishes that aging results in dysregulated SUMOylation and loss of DRH-1, which compromises antiviral defense and creates a physiological shift to favor chronic pathological infection in older animals.