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So proud of my graduate student @dommanation he solved a problem by... get this: hitting the literature!! The answer was hiding in a @Manning_BD Molecular Cell paper from 2006!
Domma is shut-out of lab work because of COVID19 shutdown, so he has been hitting the books and also learning python.. all the while we had never figured out why an AKT substrate called GSK3 stays phosphorylated during an HCMV infection setting where we know AKT is OFF
We knew from Nat Moormanās paper on the viral protein UL38, back from his days in Thomas Shenkās lab, that the HCMV virus 
protein UL38 turns off TSC2, which in turn causes mTORC1 to stay ON
protein UL38 turns off TSC2, which in turn causes mTORC1 to stay ON
Hereās Nat paper. Itās a good one! https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(08)00087-5
Anyway, we knew at a certain point that the virus (HCMV) dampens AKT activity, Domma could see this clearly by loss of P-T308 and P-S473 on AKT and loss of P-T246 PRAS40, the āProline Rich AKT substrate of 40kD.ā But GSK3, another AKT substrate was an outlier...
GSK3 (both a/b) was like the honey badger. It just donāt give AF about AKT being OFF.. it stayed phosphorylated at sites conventionally controlled by AKT... I was so dumb or at least misinformed that I even suggested he check if the viral protein kinase UL97 might be responsible
So today, after months of not knowing why GSK3 was staying phosphorylated at its AKT sites during HCMV infection, even when we know AKT is OFF, @dommanation sends me this paper https://www.sciencedirect.com/science/article/pii/S1097276506006678
So it all goes back to the viral protein UL38 forcing mTORC1 to stay active. @Manning_BDās lab showed by in ā06 that when mTORC1 is ON, S6K1 (a kinase that regulates the ribosome to stimulate protein synthesis) can substitute for AKT to phosphorylate GSK3...
Maybe this all seems silly, but we are fascinated by how viruses re-wire (hot wire!) cell pathways to their own advantage...
HCMV is clearly breaking some rules but even when it perturbs or interferes with the normal regulatory mileau, the rest of the āorderā is often still in effect.
@marcoyannic and Jonathan Weissman published a beautiful @biorxivpreprint earlier last year looking at thousands of such perturbations using single cell Seq together with CRISPR and CRISPRi https://www.biorxiv.org/content/10.1101/775080v1
Another beautiful paper published late last year came from Luis Nobre and friends in @LabWeekes https://elifesciences.org/articles/49894
Itās going to be a lot of fun to see how we can use these and other giant data sets to decipher how HCMV rewires the host cells and regulates its own behavior within them
rewires the host cells and regulates its own behavior within them
In the era of #SARSCoV2 I think we are all reminded how damn important it is to do solid, careful science on viruses and other intracellular pathogens. Thanks for attending my Ted Talk. 
#LoveVirology
#LoveVirology
