Mehle Lab
@mehlelab.bsky.social
Our small bit about flu (mostly cool stuff by lab members).
mehlelab.com
mehlelab.com
This was a very productive collaboration with labs led by Jens Kuhn and Anthony Leung. Kaitlin, Lyle, and Gloria got it off the ground, while Zhenyu and Isabel did the heavy lifting to take it across the finish line. Thanks to all authors for their effort and insight. (11/fin)
December 19, 2025 at 9:52 PM
This was a very productive collaboration with labs led by Jens Kuhn and Anthony Leung. Kaitlin, Lyle, and Gloria got it off the ground, while Zhenyu and Isabel did the heavy lifting to take it across the finish line. Thanks to all authors for their effort and insight. (11/fin)
Bottom line: ADP-ribosylation is part of an anti-viral innate immune response to flu infection, PARP1 is the enzyme responsible, and this is counteracted by a previously unknown activity of NS1. This complements anti-viral activities of ADP-ribosylation/PARPs shown for other virus families. (10/11)
December 19, 2025 at 9:52 PM
Bottom line: ADP-ribosylation is part of an anti-viral innate immune response to flu infection, PARP1 is the enzyme responsible, and this is counteracted by a previously unknown activity of NS1. This complements anti-viral activities of ADP-ribosylation/PARPs shown for other virus families. (10/11)
NS1 suppresses PARylation and this newly discovered activity requires its RNA-binding domain. The potency of this activity varies across viral strains, suggesting it may be tuned by the virus to maximize replication. (9/11)
December 19, 2025 at 9:52 PM
NS1 suppresses PARylation and this newly discovered activity requires its RNA-binding domain. The potency of this activity varies across viral strains, suggesting it may be tuned by the virus to maximize replication. (9/11)
Finally, if there is an antiviral process from the cell, you can bet that viruses have a counterpunch. Some positive-strand RNA viruses encode enzymes that remove ADPr. Instead, influenza virus fights back via its NS1 protein. (8/11)
December 19, 2025 at 9:52 PM
Finally, if there is an antiviral process from the cell, you can bet that viruses have a counterpunch. Some positive-strand RNA viruses encode enzymes that remove ADPr. Instead, influenza virus fights back via its NS1 protein. (8/11)
We showed that PARP1 is the cellular enzyme driving this defense. PARP1 directs PAR chain extension during infection, consistent with the phenotype described above. Notably, PARylation is absent and viral titers are 5x higher in PARP1 knockout cells. (7/11)
December 19, 2025 at 9:52 PM
We showed that PARP1 is the cellular enzyme driving this defense. PARP1 directs PAR chain extension during infection, consistent with the phenotype described above. Notably, PARylation is absent and viral titers are 5x higher in PARP1 knockout cells. (7/11)
When these sites are mutated to prevent modification, we saw enhanced polymerase activity. The exact mechanism of action is unclear, although it is fun to speculate that PAR chains might prevent NP from binding RNA or the viral polymerase. Lots of cellular targets also need to investigated. (6/11)
December 19, 2025 at 9:52 PM
When these sites are mutated to prevent modification, we saw enhanced polymerase activity. The exact mechanism of action is unclear, although it is fun to speculate that PAR chains might prevent NP from binding RNA or the viral polymerase. Lots of cellular targets also need to investigated. (6/11)
In one instance, we showed a direct effect where ADP-ribosylation disables the viral replication machinery. We found modification sites on nucleoprotein (NP) that appear to keep replication in check. (5/11)
December 19, 2025 at 9:52 PM
In one instance, we showed a direct effect where ADP-ribosylation disables the viral replication machinery. We found modification sites on nucleoprotein (NP) that appear to keep replication in check. (5/11)
Curiously, infection didn't cause new sites to be modified. Rather, we it caused existing mono-ADP-ribosylation modifications to be extended into longer poly(ADP-ribose) chains, intensifying the antiviral signal. Now, how does this actually stop the virus? 👇 (4/11)
December 19, 2025 at 9:52 PM
Curiously, infection didn't cause new sites to be modified. Rather, we it caused existing mono-ADP-ribosylation modifications to be extended into longer poly(ADP-ribose) chains, intensifying the antiviral signal. Now, how does this actually stop the virus? 👇 (4/11)
We mapped nearly 4,000 ADP-ribosylation sites on ~1,000 host proteins plus over 100 sites on viral proteins during infection. We’re hopeful this collection of high-quality modification sites and proteins will be useful for others studying ADP-ribosylation. (3/11)
December 19, 2025 at 9:52 PM
We mapped nearly 4,000 ADP-ribosylation sites on ~1,000 host proteins plus over 100 sites on viral proteins during infection. We’re hopeful this collection of high-quality modification sites and proteins will be useful for others studying ADP-ribosylation. (3/11)
Influenza virus must navigate the cellular environment, stealing resources it needs to replicate while avoiding host defenses. Here discovered that influenza virus infection triggers a distinct antiviral response—massive up-regulation of protein PARylation (poly-ADP-ribosylation). (2/11)
December 19, 2025 at 9:52 PM
Influenza virus must navigate the cellular environment, stealing resources it needs to replicate while avoiding host defenses. Here discovered that influenza virus infection triggers a distinct antiviral response—massive up-regulation of protein PARylation (poly-ADP-ribosylation). (2/11)
🧵 Thread on our new @natcomms.nature.com paper: TLDR -- ADP-ribosylation inhibits viral replication and represents a previously under-appreciated arm of innate immunity during flu infection. Read along for the details…. (1/11) www.nature.com/articles/s41...
Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection - Nature Communications
Influenza A virus infection causes a dramatic upregulation of ADP-ribosylation that as part of the cellular antiviral response, a process that is counteracted by the viral NS1 protein.
www.nature.com
December 19, 2025 at 9:52 PM
🧵 Thread on our new @natcomms.nature.com paper: TLDR -- ADP-ribosylation inhibits viral replication and represents a previously under-appreciated arm of innate immunity during flu infection. Read along for the details…. (1/11) www.nature.com/articles/s41...
And now the peer-reviewed published paper!! Open access for the final version. academic.oup.com/nar/advance-... Thanks again
Hutchinson, Brooke and Russell labs.
Hutchinson, Brooke and Russell labs.
Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome
Abstract. Productive infections by RNA viruses require faithful replication of the entire genome. Yet many RNA viruses also produce deletion-containing viral ge
academic.oup.com
February 26, 2024 at 8:09 PM
And now the peer-reviewed published paper!! Open access for the final version. academic.oup.com/nar/advance-... Thanks again
Hutchinson, Brooke and Russell labs.
Hutchinson, Brooke and Russell labs.
This work was led by Jordan Ranum and Mitch Ledwith, with really fruitful collaborations with the Brooke, Russell and Hutchison labs. 8/9
December 14, 2023 at 10:03 PM
This work was led by Jordan Ranum and Mitch Ledwith, with really fruitful collaborations with the Brooke, Russell and Hutchison labs. 8/9
PB2 DPRs reduce polymerase activity, suppress viral infection, and act in trans to inhibit replication of WT virus. We argue that DelVGs pack a one-two punch – both the RNA itself and the encoded DPR combine to antagonize WT virus. 7/9
December 14, 2023 at 10:03 PM
PB2 DPRs reduce polymerase activity, suppress viral infection, and act in trans to inhibit replication of WT virus. We argue that DelVGs pack a one-two punch – both the RNA itself and the encoded DPR combine to antagonize WT virus. 7/9
DPRs dramatically expand the coding space of RNA viruses. We characterized DPRs made from the polymerase subunit PB2, revealing that they are dominant negative inhibitors of polymerase assembly. 6/9
December 14, 2023 at 10:03 PM
DPRs dramatically expand the coding space of RNA viruses. We characterized DPRs made from the polymerase subunit PB2, revealing that they are dominant negative inhibitors of polymerase assembly. 6/9
…an entirely new class of protein expressed from DelVGs. We show that DelVGs are translated, producing hundreds of cryptic proteins we called DPRs (DelVG-encoded PRotein). DPRs include proteins with large internal deletions, as well as protein deletions that shift into alternative reading frames.5/9
December 14, 2023 at 10:02 PM
…an entirely new class of protein expressed from DelVGs. We show that DelVGs are translated, producing hundreds of cryptic proteins we called DPRs (DelVG-encoded PRotein). DPRs include proteins with large internal deletions, as well as protein deletions that shift into alternative reading frames.5/9
Part of this inhibition comes from the DelVG RNA itself; they compete with their full-length counterparts for replication, directly interfering with replication. DelVG RNAs can also activate antiviral responses that indirectly inhibit WT virus. Our preprint reveals another key player in this battle…
December 14, 2023 at 10:02 PM
Part of this inhibition comes from the DelVG RNA itself; they compete with their full-length counterparts for replication, directly interfering with replication. DelVG RNAs can also activate antiviral responses that indirectly inhibit WT virus. Our preprint reveals another key player in this battle…
These mistake result in point mutations. Almost all RNA viruses also make much larger mistakes, creating genomes with large internal deletions. These deletion-containing viral genomes (DelVGs) parasitize WT virus for their own propagation, and in the process poison replication of WT virus. 3/9
December 14, 2023 at 10:01 PM
These mistake result in point mutations. Almost all RNA viruses also make much larger mistakes, creating genomes with large internal deletions. These deletion-containing viral genomes (DelVGs) parasitize WT virus for their own propagation, and in the process poison replication of WT virus. 3/9
RNA viruses face a race against the clock. They must get in and out of cells before antiviral forces stop them. This prioritizes speed. But this need for speed comes at a cost – fidelity is sacrificed as the genome is copied quickly by the viral RNA-dependent RNA polymerase. 2/9
December 14, 2023 at 10:01 PM
RNA viruses face a race against the clock. They must get in and out of cells before antiviral forces stop them. This prioritizes speed. But this need for speed comes at a cost – fidelity is sacrificed as the genome is copied quickly by the viral RNA-dependent RNA polymerase. 2/9
Let's try this Bluesky for a spin -- 🚨preprint thread 🚨 1/9 www.biorxiv.org/content/10.1...
Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza...
bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution
www.biorxiv.org
December 14, 2023 at 10:00 PM
Let's try this Bluesky for a spin -- 🚨preprint thread 🚨 1/9 www.biorxiv.org/content/10.1...