A host AAA-ATPase exhibits bacteriolytic activity for clearance of microbial infection

An array of host cytosol guarding factors impede bacterial proliferation and preserve cellular sterility. Amongst them, proteasomal degradation of ubiquitinated pathogens has emerged as a critical mechanism for ensuring cytosolic sanctity. We wondered how proteasomes, with their small size and inability to extract membrane-bound proteins, can eradicate pathogens. Here, we unveil a unique strategy, wherein VCP/p97, a host AAA-ATPase, eliminates pathogens by exerting mechanical force that physically unfolds and pulls out ubiquitinated proteins from bacterial membrane. Combining a single-molecule approach along with molecular dynamic simulation and in-vitro reconstitution, we demonstrate that protein extraction by p97 causes extensive membrane lysis and release of cytosolic contents from phylogenetically diverse microbes. Additionally, in an in-vivo mouse sepsis model, this segregase-dependent bactericidal effect of p97 abrogated microbial proliferation in host tissues. Overall, we discovered a distinct innate antimicrobial function of p97, that protects the host against lethal bacterial infections. One Sentence SummaryA host AAA-ATPase exhibits bacteriolytic activity.