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<p>The complement cascade is a critical first line of defence against infections, and many viruses have evolved to block it. For example, herpes simplex virus (HSV) glycoprotein C (gC) facilitates infection by modulating the complement cascade through interaction with C3b. However, our understanding of this regulation has been limited due to the lack of a gC structure. AlphaFold predicts that gC contains a disordered N-terminus and three immunoglobulin-like domains. Using different constructs of HSV2 gC, we show that gC domains 1 and 2 are necessary and sufficient for interaction with C3b and alternative pathway inhibition. Cryo-EM of this complex provided the structure of gC, revealing that the interaction is driven by gC domains 1 and 2 and the MG8 domain of C3b. Validation by cross-linking mass spectrometry and C3b-blocking antibodies confirmed these findings. Overall, the gC-C3b interaction differs from other C3b-interacting partners, highlighting a unique mechanism for complement regulation.</p>

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Unveiling the unique interaction mechanism of herpes simplex virus 2 glycoprotein C with C3b

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Moisés Hasim Rojas Rechy,
  • Doina Atanasiu,
  • Lauren M. Hook,
  • Tina M. Cairns,
  • Wan Ting Saw,
  • Adam Cahill,
  • Zilin Guo,
  • Antonio N. Calabrese,
  • Neil A. Ranson,
  • Harvey M. Friedman,
  • Gary H. Cohen,
  • Juan Fontana

摘要

The complement cascade is a critical first line of defence against infections, and many viruses have evolved to block it. For example, herpes simplex virus (HSV) glycoprotein C (gC) facilitates infection by modulating the complement cascade through interaction with C3b. However, our understanding of this regulation has been limited due to the lack of a gC structure. AlphaFold predicts that gC contains a disordered N-terminus and three immunoglobulin-like domains. Using different constructs of HSV2 gC, we show that gC domains 1 and 2 are necessary and sufficient for interaction with C3b and alternative pathway inhibition. Cryo-EM of this complex provided the structure of gC, revealing that the interaction is driven by gC domains 1 and 2 and the MG8 domain of C3b. Validation by cross-linking mass spectrometry and C3b-blocking antibodies confirmed these findings. Overall, the gC-C3b interaction differs from other C3b-interacting partners, highlighting a unique mechanism for complement regulation.