Kaposi’s sarcoma-associated herpesvirus (KSHV) utilizes the NDP52/CALCOCO2 selective autophagy receptor to disassemble processing bodies, 2023

[SNT Gatchaman]

Kaposi's sarcoma-associated herpesvirus (KSHV) utilizes the NDP52/CALCOCO2 selective autophagy receptor to disassemble processing bodies
Robinson CA, Singh GK, Kleer M, Katsademas T, Castle EL, Boudreau BQ, Corcoran JA

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the inflammatory and angiogenic endothelial cell neoplasm, Kaposi’s sarcoma (KS). We previously demonstrated that the KSHV Kaposin B (KapB) protein promotes inflammation via the disassembly of cytoplasmic ribonucleoprotein granules called processing bodies (PBs). PBs modify gene expression by silencing or degrading labile messenger RNAs (mRNAs), including many transcripts that encode inflammatory or angiogenic proteins associated with KS disease. Although our work implicated PB disassembly as one of the causes of inflammation during KSHV infection, the precise mechanism used by KapB to elicit PB disassembly was unclear.

Here we reveal a new connection between the degradative process of autophagy and PB disassembly. We show that both latent KSHV infection and KapB expression enhanced autophagic flux via phosphorylation of the autophagy regulatory protein, Beclin. KapB was necessary for this effect, as infection with a recombinant virus that does not express the KapB protein did not induce Beclin phosphorylation or autophagic flux. Moreover, we showed that PB disassembly mediated by KSHV or KapB, depended on autophagy genes and the selective autophagy receptor NDP52/CALCOCO2 and that the PB scaffolding protein, Pat1b, co-immunoprecipitated with NDP52. These studies reveal a new role for autophagy and the selective autophagy receptor NDP52 in promoting PB turnover and the concomitant synthesis of inflammatory molecules during KSHV infection.

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[SNT Gatchaman]

Author Summary —

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several forms of cancer including Kaposi’s Sarcoma (KS). Multiple KSHV gene products contribute to inflammatory processes that sustain cancer cells. Processing bodies (PBs) are poorly characterized cellular structures that suppress inflammation by interfering with the mRNAs that encode inflammatory mediator proteins. We previously showed that a viral protein known as KapB caused PBs to disappear in KSHV infected cells. Here, we reveal the mechanism of PB disappearance in infected cells, whereby KapB co-opts the cellular catabolic process of autophagy to direct PB disassembly.

This discovery centers autophagy in viral control of inflammation and provides yet another striking example of subversion of normal cellular processes by cancer-causing viruses.

 

[rvallee]

"Most pathogens are harmless" is really going to go down in the history of medicine alongside stuff like "babies don't feel pain" and "most DNA is junk", except so much more harmful.

Because in the end it basically ignores evolution, and nothing in biology makes sense other than in the context of evolution. Life spreads, and it has no bias towards large mammals vs bits of code. Way past time we get past this hubris.