Modulation of cellular immune response by 2′-5′ Oligoadenylate Synthetase - like (OASL) proteins during DNA virus infection

Abstract

Abstract Oligoadenylate Synthetase-like (OASL) is a type I interferon (IFN) stimulated gene, strongly induced following virus infection, but lacks enzymatic activity to synthesize 2′–5′ oligoadenylates. We show that human OASL, and its functional ortholog mouse Oasl2 are critical modulators of cellular antiviral signaling. During RNA virus infection, OASL binds the RNA-sensor, RIG-I, and enhances RIG-I signaling by mimicking one of the RIG-I-ligands, K63-linked polyubiquitin [p(Ub)], thus exerting an antiviral activity. In contrast, by binding the DNA-sensor, cyclic GMP-AMP synthase (cGAS), OASL negatively regulates IFN induction and restricts inflammation in the context of DNA virus infections, some of which can establish persistent infection. Human OASL or mouse Oasl2 knockout cells showed enhanced IFN induction when stimulated either with intracellular DNA or DNA viruses such as Vaccinia and Herpes simplex virus. Consequently, Oasl2 knockout mice showed delayed and reduced Vaccinia virus spread and mortality. Additionally, OASL or Oasl2 affected IFN induction when stimulated with intracellular DNA, but not with cGAMP, indicating the upstream effect of OASL is on cGAS stimulation and not on STING stimulation. Mechanistically, OASL specifically interacted with cGAS, and inhibited its activity. Together these results establish the unique ability of OASL to differentially modulate RNA and DNA virus replication and IFN induction.