A Host AAA-ATPase Exhibits Bacteriolytic Activity for Clearance of Microbial Infection

Abstract

An array of cytosol guarding factors impede bacterial invasion and preserve cellular sterility. Amongst them, proteasomal degradation of ubiquitinated pathogens has emerged as a critical mechanism ensuring cytosolic sanctity. But smaller size of the proteasomal barrel and its inability to extract membrane-bound proteins, questions this paradigm. Our study unveiled a unique mechanical force-based strategy, employed by VCP/p97, an AAA-ATPase, which by extracting ubiquitinated bacterial surface proteins, eliminates pathogens. Using molecular dynamic simulation along with in-vitro and ex-vivo experiments, we demonstrated that p97’s segregase activity is central to its bactericidal effect. Assisted by cofactors NPLOC4 and UFD1, p97 causes extensive lysis of phylogenetically diverse microbes and triggers leaching of bacterial cytosolic contents. In-vivo, p97 abrogated bacterial proliferation in host tissues and protected animals from lethal infections. Overall, we unravelled a distinct innate immune function of p97, which is critical for host protection against bacterial infections.

Keywords: VCP/p97, AAA-ATPase, Bacterial pathogens, Ubiquitination, Cell autonomous immunity, Proteasome