That’s really interesting to use ubiquitin for replication since “ubiquitinylation” (tagging proteins with the same) is a common signal for protein destruction. Conceptually (didn’t dive into the primary source but am molec nerd), it’s like reprogramming the delete key into a copy button. Fascinating.
There's actually not that much in there about the mechanism, still in the observation stage.
>Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay.
They did a good job showing that Ub is necessary for wild-type polymerase activity, and they did a good job of modeling the interactions and structure-function relationship, which is good from a drug-design perspective. But they didn't really go into why, which is the interesting question from a strategic point-of-view.
>we found that unanchored K48-linked polyUb regulates the antiviral response by promoting IKKε activation to stimulate IFN-I responses [34], and K63-linked polyUb chains can promote RIG-I activation [31,33,53–55], and TAK1 activation [35,56,57]. On the other hand, viruses have been shown to utilize both unanchored Ub and covalent ubiquitination to replicate. In relation to unanchored Ub, Influenza viruses contain unanchored Ub in infectious virions, which can enhance virus replication by promoting uncoating via histone deacetylase 6 (HDAC6) [58,59], and other viruses may use similar mechanisms [60]
This seems counterintuitive. The ubiquitinylation is activating inflammatory response, but then why would viral polymerase activity require ubiquitin? You'd think the viruses would evolve away from inflammatory response, not towards.
> The ubiquitinylation is activating inflammatory response, but then why would viral polymerase activity require ubiquitin? You'd think the viruses would evolve away from inflammatory response, not towards.
tl;dr - Basically, this seems like it's a mechanism that is akin to the invading virus getting read access (if not root) on the cells security system, to better respond to its environment.
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It's been awhile since my biochem, but here are my thoughts tumbling around (not guaranteed correct):
- this might be like an invader noticing that the cells defences are increasing, and being able to scale it's activity with the cellular counter-response, done via activation of Ub.
- polyub chains attached to a protein are like a stronger signal for deletion. the more anchored polyUb chains, the more likely/quickly something will be tagged for removal.
- unanchored polyUb chains (that have been cut off destroyed proteins) would be a signal that a severe immune response is underway. for these free/unanchored polyUb chains to be an activator of something viral, it's the virus having a way to know when things are getting serious in the cell.
- unanchored ub might be a byproduct of a tagging. it may be active form, free-floating. High unachored ub might be product of higher transcription during stresss/inflamatory response
