The oncolytic avian reovirus p17 protein triggers chaperone-mediated autophagy by modulating Hsp90 and the T-complex protein-1 ring complex chaperones and co-chaperones to activate the IKK/NF-κB signaling

This study reveals that the oncolytic avian reovirus (ARV) p17 activates chaperone-mediated autophagy in Vero and A549 cells by modulating the Hsp90/Cdc37, T-complex protein-1 ring complex (TRiC)/Hsc70, and TRiC/phosducin-like protein 1 (PhLP1) chaperone complexes. ARV p17 enhances PhLP1 binding to TRiC, reducing TRiC/Hsc70 complex formation, which promotes IκB degradation and activates the IKK/NF-κB pathway. Additionally, p17 increases casein kinase 2 (CK2)-mediated phosphorylation, strengthening the Hsp90/Cdc37/IKK interaction and transcriptionally upregulating Beclin1, forming the Beclin1/PtdIns3K complex to further induce autophagy. Immunofluorescence shows p17-induced GFP-LC3 puncta, which decreases upon CK2 and Hsp90 knockdown. <i>In situ</i> proximity ligation assay revealed that p17 promotes LC3-II and CCT2 interactions, confirming chaperone-mediated autophagy activation. This study provides novel insights into ARV-modulated suppression of IκB by modulating co-chaperone PhLP1 and Hsc70 binding to TRiC and activation of the CK2/Hsp90/Cdc37/IKK/NF-κB pathway to induce chaperone-mediated autophagy. This work expands our understanding of the role of ARV in regulating host cell autophagy pathways and viral replication. It also provides a new avenue for understanding viral modulation of host cellular processes in the context of oncolytic virotherapy.