STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production

Li, Dapei; Wu, Rongsheng; Guo, Wenjuan; Xie, Linfeng; Qiao, Zigang; Chen, Shengchuan; Zhu, Jingfei; Huang, Chenlu; Huang, Jian; Chen, Bicheng; Qin, Yanghua; Xu, Feng; Ma, Feng

doi:10.1016/j.celrep.2019.09.069

Cited by 57 publications

(56 citation statements)

References 59 publications

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“…Therefore, it is inferred that during viral infection, IFI16 can facilitate recognition of decapsidated viral DNA in the nucleus, while cGAS in the cytoplasm engages with viral gene transcription products (104,108). However, STING signaling can trigger IFI16 degradation by tripartite motif-containing 21 (TRIM21) ubiquitination (109).…”

Section: Cross-regulation Of the Cgas-sting Pathway With Other Dna-sementioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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Section: Cross-regulation Of the Cgas-sting Pathway With Other Dna-sementioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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“…Recently, STING was shown to engage TRIM21, another E3 ubiquitin ligase, to degrade γ-interferon-inducible protein-16. 43 Our study revealed a novel B cell-intrinsic role of STING in regulating BCR signaling and plasma cell differentiation. Since continuous BCR signaling via repeated antigen binding is critical for driving plasma cell differentiation, insufficient BCR signaling in V154M B cells ( Fig.…”

Section: Discussionmentioning

confidence: 69%

STING regulates BCR signaling in normal and malignant B cells

et al. 2020

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STING is an endoplasmic reticulum (ER)-resident protein critical for sensing cytoplasmic DNA and promoting the production of type I interferons; however, the role of STING in B cell receptor (BCR) signaling remains unclear. We generated STING V154M knock-in mice and showed that B cells carrying constitutively activated STING specifically degraded membrane-bound IgM, Igα, and Igβ via SEL1L/HRD1-mediated ER-associated degradation (ERAD). B cells with activated STING were thus less capable of responding to BCR activation by phosphorylating Igα and Syk than those without activated STING. When immunized with T-independent antigens, STING V154M mice produced significantly fewer antigen-specific plasma cells and antibodies than immunized wild-type (WT) mice. We further generated B cell-specific STINGKO mice and showed that STINGKO B cells indeed responded to activation by transducing stronger BCR signals than their STING-proficient counterparts. When B cell-specific STINGKO mice were T-independently immunized, they produced significantly more antigen-specific plasma cells and antibodies than immunized STINGWT mice. Since both human and mouse IGHV-unmutated malignant chronic lymphocytic leukemia (CLL) cells downregulated the expression of STING, we explored whether STING downregulation could contribute to the well-established robust BCR signaling phenotype in malignant CLL cells. We generated a STING-deficient CLL mouse model and showed that STING-deficient CLL cells were indeed more responsive to BCR activation than their STING-proficient counterparts. These results revealed a novel B cell-intrinsic role of STING in negatively regulating BCR signaling in both normal and malignant B cells.

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“…TRIM21 mediates the polyubiquitination and degradation of the DNA sensor DDX41 and the IRF transcription factors IRF3, IRF5, and IRF7 to negatively regulate the production of interferon-β during viral infection [56]. Recent research reported that TRIM21 can also promote the STING-mediated IFI16 degradation and negatively regulate the production of type I interferon [57]. However, a growing number of studies have shown that TRIM21 positively upregulates type I IFN signaling through promoting cGAS and RIG-I sensing of viral genomes or interfering with the degradation of IRF3 and IRF8 [58,59].…”

Section: Discussionmentioning

confidence: 99%

HPV E7 inhibits cell pyroptosis by promoting TRIM21-mediated degradation and ubiquitination of the IFI16 inflammasome

Song¹,

Wu²,

Xu³

et al. 2020

Int. J. Biol. Sci.

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Human papillomavirus (HPV) is a DNA virus that causes sexually transmitted infections. The HPV oncoprotein E7 plays a critical role in the regulation of host immunity to promote the immune escape of HPV and the occurrence of cervical cancer or genital warts. Pyroptosis, a highly inflammatory form of programmed cell death, can be induced by inflammasomes and acts as a defense against pathogenic infection. However, whether HPV E7 can regulate cell pyroptosis to evade immune surveillance has not been determined. In this study, we found that HPV E7 could inhibit cell pyroptosis induced by transfection with dsDNA. The activation of the inflammasome, and the production of IL-18 and IL-1β were also restrained by HPV E7. Mass spectrometry and immunoprecipitation showed that HPV E7 interacted with IFI16 and TRIM21. We also discovered that HPV E7 recruited the E3 ligase TRIM21 to ubiquitinate and degrade the IFI16 inflammasome, leading to the inhibition of cell pyroptosis and self-escape from immune surveillance. Thus, our study reveals an important immune escape mechanism in HPV infection and may provide targets for the development of a novel immunotherapeutic strategy to effectively restore antiviral immunity.

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STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production

Abstract: Highlights d Overexpression of STING facilitates IFI16 degradation d E3 ligase TRIM21 plays a role in STING-mediated IFI16 degradation d IFI16-K3/4/6R mutation stabilizes IFI16 protein d IFI16-K3/4/6R facilitates type I IFN production

Cited by 57 publications

References 59 publications

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

STING regulates BCR signaling in normal and malignant B cells

HPV E7 inhibits cell pyroptosis by promoting TRIM21-mediated degradation and ubiquitination of the IFI16 inflammasome

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