Biology subjects

de Oliveira Mann, C. C.

Publications and source records attributed to de Oliveira Mann, C. C..

3 recordsLinked to original sources

bioRxiv2025

Profiling Nucleotide Signalling Pathways and STING Agonist Activity with a Nucleotide Library

Out of context dsDNA is detected by cGAS, which produces the cyclic dinucleotide 2'3'-cGAMP to activate STING and trigger downstream responses including transcriptional reprogramming, cell death and autophagy. STING agonists, among them non-hydrolysable cyclic dinucleotide analogues, are in active development to enhance immune activation in cancer treatment and vaccine adjuvants. Detailed knowledge of STINGs nucleotide preferences is critical for the development of effective therapeutics, yet the full spectrum of cyclic dinucleotides capable of activating STING has not been comprehensively defined. Especially considering the recent diversity of cyclic nucleotides identified across bacteria and invertebrates, the pool of potential STING agonists to be tested has expanded considerably. Here, we systematically dissect STING nucleotide preferences and distinguish STING-dependent from STING-independent nucleotide signaling pathways by treating THP-1 monocytes and pancreatic cancer cells with a nucleotide library. We identify a set of 27 cyclic dinucleotides that induce STING activation to different extents. Our data indicate that STINGs bias toward 2'3'-linked cyclic dinucleotides underlies its ability to also be activated by nucleotides containing purine-pyrimidine hybrids. In addition, we show that STING can be activated by diverse non-hydrolysable c-di-AMP and cGAMP isomers, thereby expanding the opportunities for designing STING agonists for therapeutic applications.

immunology↗

bioRxiv2025

Structural Basis for OAS2 Regulation and its Antiviral Function

Oligoadenylate synthetase (OAS) proteins are immune sensors for double-stranded RNA and critical for restricting viruses. OAS2 comprises two OAS domains, only one of which can synthesize 2-5-oligoadenylates for RNase L activation. Existing structures of OAS1 provide a model for enzyme activation, but do not explain how multiple OAS domains discriminate RNA length. Here, we discover that OAS2 exists in an autoinhibited state as a zinc-mediated dimer and present a mechanism for RNA length discrimination: the catalytically deficient domain acts as a molecular ruler that prevents autoreactivity to short RNAs. We demonstrate that dimerization and myristoylation localize OAS2 to Golgi membranes and that this is required for OAS2 activation and restriction of viruses that exploit the endomembrane system for replication, e.g. coronaviruses. Finally, our results highlight the non-redundant role of OAS proteins and emphasize the clinical relevance of OAS2 by identifying a patient with a loss-of-function mutation leading to autoimmune disease.

biochemistry↗

bioRxiv2022

Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased activity of the DNA sensor cGAS and enhanced IFN-I signature. To identify potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-{beta}, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-{beta}-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcome. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/493983v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@521964org.highwire.dtl.DTLVardef@13506org.highwire.dtl.DTLVardef@1403dbeorg.highwire.dtl.DTLVardef@958cc4_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryKessler et al. identify aberrant DNA recognition by cGAS/STING axis and IFN-I production by inflammatory macrophages as a major driver of severe ANCA-associated vasculitis (AAV). Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery, identifying potential targets for therapeutic intervention in patients.

immunology↗