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Hornung Lab - Research

Nucleic acid sensors

A common theme in pathogen defense is the recognition of nucleic acids (NA). Most pathogens expose some type of nucleic acid or degradation products thereof at some point during their life cycle (e.g. genomic DNA/RNA or RNA transcripts). To this effect, the host has evolved a number of PRRs that are specialized to sense certain components of non-self DNAs or RNAs.

Most of these NA-receptors are not PRRs in sensu stricto, as they can also respond to endogenous NAs under certain conditions. This also explains that NA-sensing PRRs often play critical roles in the initiation and perpetuation of autoimmune diseases. Indeed, bona fide NA PAMPs are rather the exception with RIG-I sensing 5’-triphosphate dsRNA and MDA5 detecting long dsRNA, both features being typical signatures of viral propagation. In fact, next to distinct structural patterns, additional principles play an important role in the context of NA detection. These include the subcellular localization and the quantity of NAs, as well as the activation threshold of the respective PRR pathways. For example, all NA-sensing toll-like receptors (TLRs) reside within the endolysosomal compartment that is usually devoid of endogenous NAs. As soon as NAs are translocated into these compartments, TLRs are engaged and trigger an immune response.

Interestingly, endolysosomal TLRs do not respond to intact nucleic acid molecules, yet they rather sense degradation products of DNA and RNA. In this regard, we recently found that TLR8 critically requires the activity of the endonuclease RNase T2 within the endolysosome to respond to complex, pathogen-derived RNA molecules. With RNase T2 being an evolutionary “ancient” enzyme that is linked to RNA catabolism, these results uncover an interesting interconnection of how nucleic acid metabolism is connected to immune defense.

Along similar lines, double-stranded DNA of both exogenous and endogenous sources is readily sensed as a sign of ‘danger’ within the cytoplasm. Here, the nucleotidyltransferase cGAS plays a pivotal role. Upon binding dsDNA, cGAS gains catalytic activity to synthesize the cyclic dinucleotide cGAMP in a two-step reaction. cGAMP, in turn, binds to and activates the ER-resident receptor molecule STING, which then oligomerizes and exits the ER towards the Golgi. STING oligomerization allows TBK1 to phosphorylate STING itself, which then serves as a docking site for IRF3, the latter being phosphorylated by TBK1 as well. Active IRF3, in turn, drives antiviral and pro-inflammatory gene expression. Another consequence of STING activation is its translocation to the lysosome, which can result in lysosomal membrane permeabilization and hence cell death. In myeloid cells, this can result in secondary engagement of the NLRP3 inflammasome and as such the maturation of pro-inflammatory IL-1 family cytokines.

Interestingly, a large proportion of cGAS is found in the nucleus where it nevertheless remains silent, despite the ample amount of nuclear DNA being present. Recent work has shown that nuclear cGAS is indeed kept in an inactive state in that it is tightly tethered to nucleosomes. This sterically hinders cGAS from being activated by dsDNA. These recent findings obviously raise the question of how this nucleosome association of cGAS is dynamically regulated in the context of immune defenses.


Recent publications in this area:

Novel Poxin Stable cGAMP-Derivatives Are Remarkable STING Agonists.
Stazzoni S, Böhmer DFR, Hernichel F, Özdemir D, Pappa A, [...] Wagner M, Veth S, Hopfner KP, Hornung V, König LM, Carell T.
Angew Chem Int Ed Engl. 2022 Jul 25:e202207175. doi: 10.1002/anie.202207175. Pubmed

Structural basis for sequestration and autoinhibition of cGAS by chromatin.
Michalski S, de Oliveira Mann CC, Stafford C, Witte G, Bartho J, Lammens K, Hornung V, Hopfner KP.
Nature. 2020 Sep 10. doi: 10.1038/s41586-020-2748-0. Pubmed

TLR8 Is a Sensor of RNase T2 Degradation Products.
Greulich W, Wagner M, Gaidt MM, Stafford C, Cheng Y, Linder A, Carell T, Hornung V.
Cell. 2019 Nov 27;179(6):1264-1275.e13. doi: 10.1016/j.cell.2019.11.001. PubMed

The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3.
Gaidt MM, Ebert TS, Chauhan D, Ramshorn K, Pinci F, Zuber S, O'Duill F, Schmid-Burgk JL, Hoss F, Buhmann R, Wittmann G, Latz E, Subklewe M, Hornung V.
Cell. 2017 Nov 16;171(5):1110-1124.e18. doi: 10.1016/j.cell.2017.09.039. PubMed

Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP.
Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, Hornung V.
Nature. 2013 Nov 28;503(7477):530-4. doi: 10.1038/nature12640. PubMed

cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING.
Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, Hopfner KP, Ludwig J, Hornung V.
Nature. 2013 Jun 20;498(7454):380-4. doi: 10.1038/nature12306. PubMed


Selected reviews in this area:

cGAS-STING signaling.
Sun Z, Hornung V.
Curr Biol. 2022 Jul 11;32(13):R730-R734. doi: 10.1016/j.cub.2022.05.027. Pubmed

Molecular mechanisms of non-self nucleic acid recognition by the innate immune system.
de Oliveira Mann CC, Hornung V.
Eur J Immunol. 2021 Jun 17. doi: 10.1002/eji.202049116. Pubmed

Molecular Mechanisms and Cellular Functions of cGAS-STING Signalling.
Hopfner KP, Hornung V.
Nat Rev Mol Cell Biol. 2020 May 18. doi: 10.1038/s41580-020-0244-x. PubMed

DNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer.
Paludan SR, Reinert LS, Hornung V.
Nat Rev Immunol. 2019 Jan 15. doi: 10.1038/s41577-018-0117-0. PubMed

Recognition of Endogenous Nucleic Acids by the Innate Immune System.
Roers A, Hiller B, Hornung V.
Immunity. 2016 Apr 19;44(4):739-54. doi: 10.1016/j.immuni.2016.04.002. PubMed

SnapShot: Nucleic acid immune sensors, part 2.
Hornung V.
Immunity, 2014; 41: 1066-1066 e1061. PubMed

SnapShot: Nucleic acid immune sensors, part 1.
Hornung V.
Immunity, 2014; 41: 868, 868 e861. PubMed

OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids.
Hornung V, Hartmann R, Ablasser A, Hopfner KP.
Nat Rev Immunol. 2014 Aug;14(8):521-8. doi: 10.1038/nri3719. Epub 2014 Jul 18. PubMed