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<p>Cell-autonomous immunity prevents intracellular pathogen growth through mechanisms such as ubiquitination and proteasomal targeting of bacteria for degradation. However, how the proteasome eradicates ubiquitinated bacteria has remained unclear. Here we show that host AAA-ATPase, VCP/p97, associates with diverse cytosol-exposed ubiquitinated bacteria (<i>Streptococcus pneumoniae</i>, <i>Salmonella enterica</i> serovar Typhimurium, <i>Streptococcus pyogenes</i>) and requires the ATPase activity in its D2 domain to reduce intracellular bacterial loads. Combining optical trap approaches along with molecular dynamic simulations, in vitro reconstitution and immunogold transmission electron microscopy, we demonstrate that p97 applies mechanical force to extract ubiquitinated surface proteins, BgaA and PspA, from <i>S. pneumoniae</i> cell membranes. This causes extensive membrane lysis and release of cytosolic content, thereby killing the pathogen. Further, p97 also controls <i>S. pneumoniae</i> proliferation in mice, ultimately protecting from fatal sepsis. Overall, we discovered a distinct innate antimicrobial function of p97 that can protect the host against lethal bacterial infections.</p>

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Host AAA-ATPase VCP/p97 lyses ubiquitinated intracellular bacteria as an innate antimicrobial defence

  • 期刊论文

  • 发表日期：

    2025年4月11日

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  • Sourav Ghosh,
  • Suvapriya Roy,
  • Navin Baid,
  • Udit Kumar Das,
  • Sumit Rakshit,
  • Paulomi Sanghavi,
  • Dipasree Hajra,
  • Sayani Das,
  • Sneha Menon,
  • Mohammad Sahil,
  • Sudipti Shaw,
  • Raju S. Rajmani,
  • Harikrishna Adicherla,
  • Sandip Kaledhonkar,
  • Jagannath Mondal,
  • Dipshikha Chakravortty,
  • Roop Mallik,
  • Anirban Banerjee

摘要

Cell-autonomous immunity prevents intracellular pathogen growth through mechanisms such as ubiquitination and proteasomal targeting of bacteria for degradation. However, how the proteasome eradicates ubiquitinated bacteria has remained unclear. Here we show that host AAA-ATPase, VCP/p97, associates with diverse cytosol-exposed ubiquitinated bacteria (Streptococcus pneumoniae, Salmonella enterica serovar Typhimurium, Streptococcus pyogenes) and requires the ATPase activity in its D2 domain to reduce intracellular bacterial loads. Combining optical trap approaches along with molecular dynamic simulations, in vitro reconstitution and immunogold transmission electron microscopy, we demonstrate that p97 applies mechanical force to extract ubiquitinated surface proteins, BgaA and PspA, from S. pneumoniae cell membranes. This causes extensive membrane lysis and release of cytosolic content, thereby killing the pathogen. Further, p97 also controls S. pneumoniae proliferation in mice, ultimately protecting from fatal sepsis. Overall, we discovered a distinct innate antimicrobial function of p97 that can protect the host against lethal bacterial infections.