Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division

Abstract

Extracellular matrix (ECM) elasticity is perceived by cells via focal adhesion structures, which transduce mechanical cues into chemical signalling to conform cell behaviour. Although the contribution of ECM compliance to the control of cell migration or division has been extensively studied, little has been reported regarding infectious processes. We have studied how mechanical properties of the ECM impact invasion of cells by the extraintestinal Escherichia coli pathogen UTI89. We show that UTI89 takes advantage, via its CNF1 toxin, of integrin mechanoactivation to trigger its invasion into cells. We identified OPTN as a protein regulated by ECM stiffness whose function is required for bacterial invasion and integrin mechanical coupling and for stimulation of HACE1 E3 ligase activity towards the Rac1 GTPase. We showed that OPTN knockdown cells display enhanced Rac1 activation, strong mechanochemical adhesion signalling and increased cyclin D1 translation, together with enhanced cell proliferation independent of ECM stiffness. Despite such features, OPTN knockdown cells displayed defective traction force buildup associated with limited cellular invasion by UTI89. Together, our data indicate that OPTN, through a new role in mechanobiology, supports CNF1-producing uropathogenic E. coli invasion and links HACE1-mediated ubiquitylation of Rac1 to ECM mechanical properties and integrin mechanotransduction.

The cnf1 gene is associated with an expanding Escherichia coli ST131 H 30Rx/C2 subclade and confers a competitive advantage for gut colonization

“… 19 , 23 , 50 , 51 In line with this, CNF1 deamidase exacerbates Rho GTPase signaling, and notably Rac1, to promote type I pili-mediated host cell invasion. 52 , 53 Enhanced capacities to invade and colonize intestinal tissues may also involve factors encoded within PAI II EC131GY -like from ST131 H 30Rx/C2. Indeed, cnf1 -bearing PAIs contain a core set of genes encoding the F17-like pili, the P-fimbriae tipped with PapG class II adhesin, and the HlyA toxin, as well as a gene encoding hemagglutinin in E. coli K1 (Hek).…”