The innate immune system is a first line of defense against invading pathogens. The innate immune system against virus infections is poorly understood on a systems level, because it is unclear how viruses are sensed in a qualitative and quantitative manner by RIG-I like receptors (RLRs). Although RIG-I ligands are characterized in vitro, it is unclear what RNA molecules are detected inside a living cell by RLRs and how different RLRs cooperate to initiate a sensitive but robust response. We aim at proceeding from the structural mechanistic knowledge to an understanding how RLRs interact with viral and cellular RNA on a systems level. We established the PAR-CLIP method to be used with virus infected cells and are now in an excellent position to study where RIG-I like receptors interact with different viral genomes in vivo using deep sequencing. This should clarify which epitopes and RNA molecules are differentially detected by different RLRs in a virus specific manner and also reveal the enigmatic MDA5 and LGP2 ligands. Mutations that trap RLRs in functional states will address whether the poorly understood ATPase activities of RLRs increase the signal-to-noise of the system. The long-term goal is to understand how quantitative and qualitative interactions of RLRs with their ligands are correlated with the strength of interferon production.

Simon Runge

Charlotte Lässig

Hornung V, Hartmann R, Ablasser A, Hopfner KP (2014). OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids. Nat Rev Immunol 14(8):521-8.

Hopfner KP (2014). Single-molecule choreography between telomere proteins and G quadruplexes. Structure 22(6):801-2.

Runge S, Sparrer KM, Lässig C, Hembach K, Baum A, García-Sastre A, Söding J, Conzelmann KK, Hopfner KP (2014). In vivo ligands of MDA5 and RIG-I in measles virus-infected cells. PLoS Pathog 10(4):e1004081.

Tosi A, Haas C, Herzog F, Gilmozzi A, Berninghausen O, Ungewickell C, Gerhold CB, Lakomek K, Aebersold R, Beckmann R, Hopfner KP (2013). Structure and subunit topology of the INO80 chromatin remodeler and its nucleosome complex. Cell 154(6):1207-19. 

Motz C, Schuhmann KM, Kirchhofer A, Moldt M, Witte G, Conzelmann KK, Hopfner KP (2013). Paramyxovirus V proteins disrupt the fold of the RNA sensor MDA5 to inhibit antiviral signaling. Science 339(6120):690-3.

1: Wollmann P, Cui S, Viswanathan R, Berninghausen O, Wells MN, Moldt M, Witte G, Butryn A, Wendler P, Beckmann R, Auble DT, Hopfner KP. Structure and mechanism of the Swi2/Snf2 remodeller Mot1 in complex with its substrate TBP. Nature. 2011 475:403-7

2: Lammens K, Bemeleit DJ, Möckel C, Clausing E, Schele A, Hartung S, Schiller CB, Lucas M, Angermüller C, Söding J, Strässer K, Hopfner KP. The Mre11:Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair. Cell. 2011 Apr 1;145(1):54-66.

3:Hartung S, Niederberger T, Hartung M, Tresch A, Hopfner KP. Quantitative analysis of processive RNA degradation by the archaeal RNA exosome. Nucleic Acids Res. 2010 Aug;38(15):5166-76.

4:Myong S*, Cui S, Cornish PV, Kirchhofer A, Gack MU, Jung JU, Hopfner KP*, Ha T*. Cytosolic viral sensor RIG-I is a 5'-triphosphate-dependent translocase on double-stranded RNA. Science. 2009 Feb 20;323(5917):1070-4. (* co-corresponding)

5: Witte G, Hartung S, Büttner K, Hopfner KP. Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates. Mol Cell. 2008 Apr 25;30(2):167-78.

6: Cui S, Eisenächer K, Kirchhofer A, Brzózka K, Lammens A, Lammens K, Fujita T, Conzelmann KK, Krug A, Hopfner KP. The C-terminal regulatory domain is the RNA 5'-triphosphate sensor of RIG-I. Mol Cell. 2008 Feb 1;29(2):169-79.

7: Büttner K, Nehring S, Hopfner KP. Structural basis for DNA duplex separation by a superfamily-2 helicase. Nat Struct Mol Biol. 2007 Jul;14(7):647-52

8: Alt A, Lammens K, Chiocchini C, Lammens A, Pieck JC, Kuch D, Hopfner KP*, Carell T*. Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta. Science. 2007 Nov 9;318(5852):967-70. (* co-corresponding)

9: Büttner K, Wenig K, Hopfner KP. Structural framework for the mechanism of archaeal exosomes in RNA processing. Mol Cell. 2005 Nov 11;20(3):461-71.

10: Dürr H, Körner C, Müller M, Hickmann V, Hopfner KP. X-ray structures of the Sulfolobus solfataricus SWI2/SNF2 ATPase core and its complex with DNA. Cell. 2005 121:363-73.