The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) detects microbial and self-DNA in the cytosol to activate immune and inflammatory programs. cGAS also associates with chromatin, especially after nuclear envelope breakdown when cells enter mitosis. How cGAS is regulated during cell cycle transition is not clear. Here, we found direct biochemical evidence that cGAS activity was selectively suppressed during mitosis in human cell lines and uncovered two parallel mechanisms underlying this suppression. First, cGAS was hyperphosphorylated at the N terminus by mitotic kinases, including Aurora kinase B. The N terminus of cGAS was critical for sensing nuclear chromatin but not mitochondrial DNA. Chromatin sensing was blocked by hyperphosphorylation. Second, oligomerization of chromatin-bound cGAS, which is required for its activation, was prevented. Together, these mechanisms ensure that cGAS is inactive when associated with chromatin during mitosis, which may help to prevent autoimmune reaction.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171060 | PMC |
| http://dx.doi.org/10.1126/science.abc5386 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Assignment of the N-terminal domain of mouse cGAS.
Biomol NMR Assign
January 2025
Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
Cyclic GMP-AMP synthase (cGAS) is a DNA-sensing enzyme that is a member of the nucleotidyltransferase (NTase) family and functions as a DNA sensor. The protein is comprised of a catalytic NTase core domain and an unstructured hypervariable N-terminal domain (NTD) that was reported to increase protein activity by providing an additional DNA-binding surface. We report nearly complete H, N, and C backbone chemical-shift assignments of mouse cGAS NTD (residues 5-146), obtained with a set of 3D and 4D solution NMR experiments.
View Article and Find Full Text PDFMacrophage STING signaling promotes fibrosis in benign airway stenosis via an IL6-STAT3 pathway.
Nat Commun
January 2025
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
Acute and chronic inflammation are important pathologies of benign airway stenosis (BAS) fibrosis, which is a frequent complication of critically ill patients. cGAS-STING signalling has an important role in inflammation and fibrosis, yet the function of STING in BAS remains unclear. Here we demonstrate using scRNA sequencing that cGAS‒STING signalling is involved in BAS, which is accompanied by increased dsDNA, expression and activation of STING.
View Article and Find Full Text PDFAnti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer's disease.
Cell Rep
December 2024
School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA. Electronic address:
Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples.
View Article and Find Full Text PDFBioactive microspheres to enhance sonodynamic-embolization-metalloimmune therapy for orthotopic liver cancer.
Biomaterials
December 2024
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China. Electronic address:
The development of novel microspheres for the combination of sonodynamic therapy (SDT) with transarterial embolization (TAE) therapy to amplify their efficacy has received increasing attention. Herein, a novel strategy for encapsulating sonosensitizers (e.g.
View Article and Find Full Text PDFUSP34 regulates PIN1-cGAS-STING axis-dependent ferroptosis in cervical cancer via SUMOylation.
Int Immunopharmacol
January 2025
Department of Gynecology, Dalian Women and Children's Medical Center (Group), Dalian Medical University, Dalian 116033, Liaoning, China. Electronic address:
Background: Cervical cancer is a prevalent form of cancer in women, and the inhibition of ferroptosis has been shown to promote the progression of cervical cancer tumours. This study aimed to investigate the role of PIN1 in regulating ferroptosis in cervical cancer, focusing on its ability to modulate the cGAS-STING pathway and the potential involvement of USP34 as an upstream regulator of PIN1.
Methods: PIN1-overexpressing and PIN1-knockdown cell lines were constructed.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!