Hell of a way for a cell to defend itself

Imagine it’s Dodge City in the 1880’s and rustlers and gunslingers are shooting up the town.  What do Wyatt Earp and Bat Masterson do?  They don’t call in the cavalry.  They open the jail.   With the town in flames the army moves in, destroying much of the town in the process.

Crazy?  Yes.  But this is a pretty good analogy to how retroviruses are used to help fight off infection if Proc. Natl. Acad. Sci. vol. 116 pp. 17399 – 17408 ’19 is correct

Endogenous retroviruses constitute around 10% of our genome — that’s 320,000,000 nucleotides. Normally they are kept locked up in a tightly condensed mess of DNA and proteins called heterochromatin, so their genome can’t be transcribed and cause trouble.  It takes a lot to lock them up — TRIM28 acting in concert with zinc finger proteins, SUMO, a histone methyltransferase (SETDB1) and last but not least NuRD (not NeRD) — Nucleosome Remodeling and Deacetylation complex.

But when a variety of cells are infected with a variety of influenza viruses, they are let loose because the heterochromatin breaks up, the endogenous retroviruses are freed producing lots of double stranded RNA.  This is sensed as nonSelf, by Pattern Recognition Receptors (PRRs) strongly activating antiviral immunity.

The key thing in the repressive complex is SUMO, a protein resembling ubiquitin which gloms onto lysines like ubiquitin.  To be efficient in repressing the retroviruses, TRIM28 must be SUMOylated.  In some way influenza virus infection results in nonSUMOylated TRIM28.  The authors note that the mechanism of the switch in SUMOylation status ‘has yet to be precisely defined’.  I’m sure the authors are working on it, but who in the world would have thought that cells would use retroviruses as a defense mechanism.  Not me, certainly.

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