Rac1 E3 ubiquitin-ligase in bacterial invasion and inflammation – RacLig-HPI

The extensive increase of the human life span largely reflects progresses achieved in the fight against pathogenic bacteria responsible for acute infectious diseases through implementation of vaccination and antibiotherapy. By turn, these achievements have led to a new combining of medical problems due to pathogen persistence and recurrent infections leading to chronic inflammatory diseases. A common theme to all inflammatory diseases is that the inflammatory response, originally aimed at recognizing and eliminating foreign “pathogens” or damaging agents, overreacts to them and causes tissue damage that can be detrimental to the patient. How to limit such overreaction without compromising the efficiency of the defense response is a challenge faced by scientists and clinicians working in this field.
We are decrypting the host-pathogen interaction controlled by a small GTPase of the Rho protein family, Rac1, to decipher important negative regulators of this master regulator of inflammation and key host factor targeted by pathogen in bacterial invasion.
Indeed, dysfunction of Rac1 signaling pathways is implicated in severe human diseases, such as immunological disorders, infections, cancer and mental retardation. An outstanding question in microbiology has arisen from reports indicating that several pathogenic bacteria have evolved virulence factors directed towards Rho GTPases, notably Rac1. Study of this crosstalk has established Rho proteins, most notably Rac1, as central element of the host defenses against pathogens. Importantly, Rac1 controls inflammatory responses, phagocytosis and reactive oxygen species production but is also hijacked by several pathogenic bacteria to invade host cells and tissues. One central question is raised by the findings that both activating and inactivating virulence factors that target Rho GTPases coexist in pathogenic bacteria. In line with this, our group has established that the CNF1 toxin of uropathogenic Escherichia coli, a major pathogen of nosocomial and recurrent infections, triggers a permanent activation of Rho GTPases, maximal for Rac1, that is balanced in cells by the sensitization of these GTPases to ubiquitin-mediated proteasomal degradation (Flatau, 1997 Nature; Doye, 2002 Cell). Despite the discovery of this new major mode of regulation of Rac1, the E3 ubiquitin ligase responsible for its ubiquitylation remains to be characterized. Further studies on this major regulation will likely clarify a major pathway of cell invasion by pathogenic bacteria and inflammation controlled by Rac1 and will be of potential use in vaccinology considering our discovery of the adjuvant properties of Rho protein activation for mucosal vaccination.