Abstract
The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. By performing mass spectrometry, we identified Lys231 and Lys421 as essential neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.
Highlights
Innate immunity plays pivotal roles in pathogen defense and tissue repair
To determine whether neddylation modulates the cGAS-stimulator of interferon genes (STING) pathway, we first examined potential changes in various immune responses triggered by cGAS-STING activation upon blockage of neddylation modification in human and mouse cells
To further confirm these results, we measured the potential changes of innate immune response after knockdown of Uba3, the catalytic subunit of NEDD8 activating enzyme to which MLN4924 inhibits [13,19]
Summary
Innate immunity plays pivotal roles in pathogen defense and tissue repair. It is mainly achieved by pattern recognition receptors (PRRs), which detect pathogen associated molecular patterns (PAMPs, from pathogens) and danger-associated molecular patterns (DAMPs, from host) to evoke instant activation of innate immunity and the subsequent adaptive immunity [1,2,3].Nucleic acids have been defined as a fundamental mechanism to elicit innate immunity by a heterogeneous group of PRRs. Innate immunity plays pivotal roles in pathogen defense and tissue repair. It is mainly achieved by pattern recognition receptors (PRRs), which detect pathogen associated molecular patterns (PAMPs, from pathogens) and danger-associated molecular patterns (DAMPs, from host) to evoke instant activation of innate immunity and the subsequent adaptive immunity [1,2,3]. The cGAS-STING pathway is an important component of the innate immunity against pathogen infection, with the fact that cGAS or STING deficiency mice are unable to induce type I interferon and susceptible to DNA viruses or Listeria monocytogenes [6,7]. The inappropriate activation of the cGAS–STING pathway may initiate autoimmune diseases or exacerbate non-infectious inflammation, so its activation should be tightly regulated within a proper scope [8,9,10]
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