Chlamydial protease-like activating factor targets SLC7A11 for degradation to induce ferroptosis and facilitate dissemination

Abstract

AbstractChlamydia trachomatis, the most prevalent bacterial agent of sexually transmitted infections, possesses remarkable capacities for dissemination within the host, leading to reproductive health complications. The release of progeny through the orchestrated lysis of host cells plays a crucial role inChlamydiadissemination, but the underlying molecular mechanisms remain largely elusive. Here, we uncovered a novel mechanism by whichChlamydiainduces host cells ferroptosis to facilitate its dissemination. This process involves the degradation of host protein SLC7A11 by the chlamydial protease-like activating factor (CPAF), resulting in glutathione depletion, oxidative damage, and subsequent host cell lysis characterized by lipid peroxidation. Infection with CPAF-deficient strain fails to induce host cells ferroptosis, leading to restricted progeny release. Importantly, inhibiting ferroptosis effectively limits the release ofChlamydiaprogeny, highlighting its potential as a therapeutic strategy for controllingChlamydiadissemination. These findings provide insights into the chlamydial conserved dissemination strategy and enhance understanding of its pathogenesis.