Fig. 1

Cytoplasmic nucleic acid-sensing pathways. After RNA virus infection of mammalian cells, the invading vRNA is sensed by RLRs, which include RIG-I and MDA5, in the cytoplasm. After sensing vRNA, RLRs are translocated to mitochondria, where they interact with VISA. VISA then recruits WDR5 and TRAF proteins, the kinases TBK1 and IKK, and the transcription factors IRF3 and NF-κB. In these complexes, activated TBK1 and IKK phosphorylate and activate IRF3 and NF-κB, respectively, leading to their translocation into the nucleus and expression of downstream antiviral genes. After DNA virus infection of mammalian cells, vDNA is sensed by cGAS. After binding to cytosolic DNA, cGAS catalyzes the synthesis of cGAMP from the substrates GTP and ATP. cGAMP binds to MITA/STING at the endoplasmic reticulum (ER), which promotes MITA/STING oligomerization and trafficking from the ER to perinuclear punctate structures. During trafficking, MITA/STING recruits TBK1 and IRF3, leading to IRF3 phosphorylation, dimerization and translocation into the nucleus to drive the transcription of type I IFN genes. Additionally, NF-κB is activated by the MITA/STING-associated complex, leading to the transcription of inflammatory cytokine genes. The cGAS-MITA/STING axis is extensively regulated by cofactors, such as ZCCHC3, G3BP1, PCBP1, ZDHHC1, iRhom2 and ARMH3. Some AT-rich viral DNA sequences can be transcribed to vRNA by RNA polymerase III, and they are sensed by RIG-I to initiate innate immune signaling. Infection with certain RNA or DNA viruses causes mtDNA release from mitochondria into the cytosol, which triggers the innate immune response via the cGAS-MITA/STING axis. Cytoplasmic RNA- and DNA-sensing pathways are common used in host cells and antagonize either RNA or DNA viruses. RIG-I retinoic acid-inducible gene I; MDA5 melanoma differentiation-associated protein 5; VISA virus-induced signaling adaptor; WDR5 WD repeat-containing protein 5; TRAF TNF receptor-associated factor; TBK1 TANK-binding kinase 1; IKK inhibitor of nuclear factor kappa-B kinase; IRF3 interferon regulatory factor 3; cGAS cyclic GMP-AMP synthase; MITA mediator of IRF3 activation; STING stimulator of interferon gene; ZCCHC3 zinc finger CCHC ___domain-containing protein 3; G3BP1 GTPase activating protein (SH3 ___domain) binding protein 1; PCBP1 Poly(rC)-binding protein 1; ZDHHC1 zinc finger DHHC ___domain-containing protein 1; iRhom2 inactive rhomboid protein 2; ARMH3 Armadillo-like helical ___domain-containing protein 3