Editors' ChoiceImmunology

Nuclear jailbreak: DNA escapes and inflames

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Science Translational Medicine  18 Oct 2017:
Vol. 9, Issue 412, eaap8171
DOI: 10.1126/scitranslmed.aap8171

Abstract

Cytosolic DNA sensors detect fragmented or damaged DNA that escapes the nucleus during cellular senescence or cancer and induces inflammation.

Genomic DNA, the heritable code for life, is protected by a specialized nuclear envelope inside each cell. Outside this barrier in the cytosol, cells have evolved a defense system that senses double-stranded DNA from invading pathogens, such as DNA viruses or intracellular bacteria. The cytosolic patrolling machinery begins with cGAS [cyclic guanosine monophosphate—adenosine monophosphate (GMP-AMP) synthase], a protein that, upon binding double-stranded DNA in a sequence-independent fashion, catalyzes synthesis of a small gap junction permeable cyclic dinucleotide, cGAMP (cyclic GMP-AMP). cGAMP then signals via the adaptor STING (stimulator of interferon genes) to initiate inflammation and interferon-dependent antiviral programs via the transcription regulators nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3). Growing evidence suggests that self-DNA can escape the nuclear compartment under certain circumstances, raising the possibility that self-DNA may autoactivate immune responses in diseases. Dou and colleagues now explore the consequences of escaped self-DNA in senescence and cancer.

The team observed that cytoplasmic chromatin fragments (CCF) can pinch off from intact nuclei during senescence, a cancer- and aging-associated stress response characterized by loss of nuclear lamina protein lamin B1, destabilization of the nuclear envelope, and production of inflammatory cytokines termed the senescence associated secretory phenotype (SASP). Inducing senescence by oncogenic Ras; radiation- or chemical-induced DNA damage; or replication exhaustion caused fragmented self-DNA, co-localization with cGAS, increased cGAMP, and led to aggregation of STING homodimers and production of NF-κB–regulated cytokines, such as interleukin-1α. Somewhat surprisingly, the IRF3- and interferon-dependent arm of STING-signaling was not induced by senescence. Cell lines with decreased DNA sensing machinery (cGAS or STING) or increased nuclear stabilizing protein (lamin B1) showed reduced NF-κB activity and SASP after DNA damage. In vivo, genetic deficiency of STING reduced radiation-induced inflammation in the liver compared with wild type mice. STING-null mice exhibited less inflammation after oncogenic Ras-mediated senescence, which was associated with reduced senescent cell clearance and emergence of intrahepatic tumors—an effect that was rescued by re-expression of STING. Human cancers known to evade host immune responses had similarly detectable CCF but notably lacked expression of SASP-associated inflammatory genes. Across multiple databases, the highest cGAS- and STING-expressing samples, and the lowest lamin B1-expressing samples, exhibited the highest expression of NF-κB–regulated inflammatory cytokines.

This work adds to a growing body of evidence linking nuclear escape of self-DNA to cGAS- and STING-dependent autoinflammation. It also suggests that small molecule modulators of cGAS and STING may have roles in senescence-dependent pathologies, such as aging.

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