Hepatitis C Protein NS5A Stops YAP1 Breakdown by Blocking Its Interaction with a Cellular Helper

The R327A/Q328A mutant of YAP1 exhibited the greatest reduction in binding to HSC70, indicating that the sequence ELLRQ functions as a KFERQ motif in YAP1.

• Hepatitis C virus (HCV) infection triggers chaperone-mediated autophagy (CMA), facilitated by the NS5A protein.
• The YAP1 protein contains a KFERQ motif, which is recognized by the molecular chaperone HSC70 for degradation.
• Mutants of YAP1 with alterations in the KFERQ motif were generated to assess binding to HSC70.
• Knockdown of LAMP2A led to increased levels of YAP1, confirming YAP1's role as a CMA substrate.
• HSC70 interacts with phosphorylated YAP1 at serine 127, although NS5A does not bind directly to YAP1.
• NS5A expression reduces the interaction between YAP1 and HSC70, resulting in YAP1 accumulation and potential activation of genes related to cell proliferation.

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