Forward or backward, that is the question: phospholipid trafficking by the Mla system.

The distinctive feature of Gram-negative bacteria is the presence of an asymmetric outer membrane (OM), which acts as a permeation barrier blocking the diffusion of noxious components such as antibiotics that could compromise cell survival. The outer membrane has an inner leaflet, mainly formed by phospholipids (PLs), and the outer leaflet, composed of molecules of lipopolysaccharide (LPS). Building this membrane is a very complex process as every OM element needs to be transported from the cytoplasm or the inner membrane and properly placed in the OM. In addition, the asymmetry needs to be maintained to guarantee the barrier function of the membrane. The presence of misplaced PLs in the outer leaflet of the OM causes increased permeability, endangering cell survival. The Mla system (maintenance of OM lipid asymmetry) has been linked to the removal of the misplaced PLs, restoring OM asymmetry. The Mla system has elements in all compartments of the cell envelope: the lipoprotein MlaA in complex with the trimeric porins OmpC/F in the OM, MlaC in the periplasmic space and an ABC transporter in the inner membrane called MlaFEDB. While genetic and structural work suggest that the Mla pathway is retrograde (PL movement from OM to IM), several groups have advocated that transport could happen in an anterograde fashion (from IM to OM). However, recent biochemical studies strongly support retrograde transport. This review provides an overview of the current knowledge of the Mla system from a structural point of view and addresses the latest biochemical findings and their impact in transport directionality.