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<p>Orthoflaviviruses, such as tick-borne encephalitis virus (TBEV) and West Nile virus (WNV), can cause severe neurological disease and remain without specific antiviral treatments. We found that orthoflavivirus envelope (E) and non-structural protein 1 (NS1) interact with heat shock protein 70 (Hsp70) chaperones, key regulators of protein homeostasis and existing cancer drug targets. We examined how Hsp70 and endoplasmic reticulum–resident BiP contribute to viral protein secretion and infectivity of tick and mosquito-borne orthoflaviviruses. Targeting the Hsp70 nucleotide-binding domain with small-molecule inhibitor YM-1 significantly reduced infectivity of multiple orthoflaviviruses, while substrate-binding domain inhibitor PES-Cl specifically impaired NS1 secretion of tick-borne orthoflaviviruses. Protein degradation inhibitors restored NS1 expression in BiP-deficient cells but failed to rescue NS1 secretion. These data indicate that while BiP is essential for secretion of tick-borne orthoflavivirus NS1, it is not required for infectivity. The antiviral effect of YM-1 likely reflects inhibition of other chaperones or additional cellular targets.</p>

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Divergent roles of Hsp70 chaperones in orthoflavivirus protein secretion and virion formation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • Lea Blank,
  • Christin Lorenz,
  • Imke Steffen

摘要

Orthoflaviviruses, such as tick-borne encephalitis virus (TBEV) and West Nile virus (WNV), can cause severe neurological disease and remain without specific antiviral treatments. We found that orthoflavivirus envelope (E) and non-structural protein 1 (NS1) interact with heat shock protein 70 (Hsp70) chaperones, key regulators of protein homeostasis and existing cancer drug targets. We examined how Hsp70 and endoplasmic reticulum–resident BiP contribute to viral protein secretion and infectivity of tick and mosquito-borne orthoflaviviruses. Targeting the Hsp70 nucleotide-binding domain with small-molecule inhibitor YM-1 significantly reduced infectivity of multiple orthoflaviviruses, while substrate-binding domain inhibitor PES-Cl specifically impaired NS1 secretion of tick-borne orthoflaviviruses. Protein degradation inhibitors restored NS1 expression in BiP-deficient cells but failed to rescue NS1 secretion. These data indicate that while BiP is essential for secretion of tick-borne orthoflavivirus NS1, it is not required for infectivity. The antiviral effect of YM-1 likely reflects inhibition of other chaperones or additional cellular targets.