Indra_Beķere

Finding a foothold to fight: New insights into the viral RNA sensing and activation mechanism of OAS2 Oligoadenylate synthetases (OASs) are a family of double-stranded RNA (dsRNA)-activated nucleotidyltransferases involved in pathogen sensing and innate immune response. In this issue of Molecular Cell, Merold et al. define a mechanism of OAS2 activation by dsRNA-length discrimination and its deficiency associated with autoimmune disorder.

Finding a foothold to fight: New insights into the viral RNA sensing and activation mechanism of OAS2

Congratulations! 🎉

Especially our collaborators @sparrerlab.bsky.social, Andreas Pichlmair, Katja Lammens, Lars König, Dorota Kmiec, Nadine Schwierz and Min Ae Lee-Kirsch!

Our manuscript on dsRNA sensor OAS2 from the lab of @oliveiramann.bsky.social is now out in @cp-molcell.bsky.social ! Thanks again to the whole team for their effort putting this story together!

Thrilled to see my postdoc work at Adelman Lab @hms-bcmp.bsky.social on Integrator(INT) now out @cp-cell.bsky.social. We found that INT deficiency allows immature+unlicensed RNAPII to precociously enter genes. This immature RNAPII can transcribe short genes but terminates prematurely in long genes:

In search of molecular switches in the immune system A decades-long search culminated in 2013 with the discovery of cGAS – a molecular switch that plays a key role in the human immune system. Carina Baer de Oliveira Mann was a doctoral student with the ...

Meet Carina Baer de Oliveira Mann, our newly appointed professor of #Biomolecular Cryo-Electron Microscopy, in the latest NewIn episode. She aims to identify #molecularswitches in the human #immunesystem that activate the immune defenses: go.tum.de/157504

@oliveiramann.bsky.social
🎥ProLehre

Happy to share the first preprint from my lab by
@indrabekere.bsky.social and Veronika Merold! We solved the cryo-EM structure of the RNA immune sensor OAS2 and revealed how dimerization and subcellular localization regulate its activity!

Check out Indra’s thread for a summary:

Structural Basis for OAS2 Regulation and its Antiviral Function https://www.biorxiv.org/content/10.1101/2025.01.28.635220v1

To sum up, our data bring a lot of new interesting insights in biology of OAS2. All this would not be possible without our collaborators Andreas Pichlmair, @sparrerlab.bsky.social ,Nadine Schwierz, Min Ae Lee-Kirsch and Lars Koening. Happy reading!

Finally, we also show a novel heterozygous OAS2 LOF mutation F524L leading to autoimmunity in a child. In our structure, we map this residue to the catalytic domain II, which is strongly conserved across species and in other NTases and explains why mutation destabilizes OAS2.

We did an extensive virus screen and found that OAS2 restricts viruses that replicate using endomembrane system forming double membrane vesicles. Only OAS2 WT that is dimeric and localized to golgi is able to restrict viruses showing that oligomeric state and location are key!

Using our structure, we designed other mutations to just destabilize the dimer conformation and this led to increased activity, confirming that disruption of dimeric state is needed for activation.

In cells OAS2 protein is targeted to golgi via N-terminal myristoylation. Surprisingly, disrupting golgi targeting completely abolishes the activity. Monomeric OAS2 was mislocalized and less active showing that oligomeric state and localization regulate activity.

We show a novel non-canonical dsRNA-binding interface in catalytically inactive domain DI. DI works like a molecular ruler, that measures RNA length which must be of certain minimal length to bind this interface and open up the inactive dimer conformation.

We next show that OAS2 prefers longer RNAs and that monomeric OAS2 can be activated already by shorter RNAs. But why does OAS2 require dsRNA of a certain minimal length for activation?

Vroni set out to solve the first cryo-EM structure of apo OAS2 which showed a dimer in inactive conformation mediated by an unexpected Zinc atom interaction with histidine and cysteine residues. Mutating the key Zinc-interacting Cysteine made OAS2 monomeric and hyperactive!

Oligoadenylate synthetase 1-3 (OAS1-3) proteins are important dsRNA-sensors in antiviral immunity with recently identified relevance in SARS-CoV2 infection and MIS-C syndrome. But we know very little about how OAS proteins are regulated, especially OAS2

I’m very excited to share our first preprint “Structural Basis for OAS2 Regulation and its Antiviral Function” from my postdoc together with Veronika Merold (Vroni) from NTase lab with @oliveiramann.bsky.social www.biorxiv.org/content/10.1...