The Legionella pneumophila Dot/Icm type IV secretion system: The core subcomplex and the coupling protein subcomplex

Legionella pneumophila is a respiratory pathogen that is able to cause disease by replicating inside alveolar macrophages. The bacteria accomplish this by altering the endocytic pathway of the host cell, thereby establishing a unique intracellular compartment known as the replicatine phagosome. L. pneumophila employs a specialized secretion system, the Dot/Icm type IV secretion system, to mediate intracellular survival and growth. To understand the molecular mechanisms of L. pneumophila pathogenesis, we have focused on characterizing how the Dot/Icm secretion system functions to deliver substrates into host cells via an extensive biochemical and genetic analysis. Two subassemblies of Dot/Icm proteins have been identified, one is composed of the DotC, DotD, DotF, DotG, and DotH proteins, and the second is composed of DotL, DotM, DotN, IcmS, IcmW, and LvgA.; The first subcomplex consists of five proteins and spans the inner and outer membranes of the bacterial cell. This transmembrane connection is mediated by heterodimer pairs of the inner membrane proteins DotF and DotG, which independently associate with DotH, DotC, and DotD in the outer membrane. We propose that DotH may function similarly to secretios in other secretion systems, forming oligomeric channels in the outer membrane through which substrates are transported. By bridging the two bacterial membranes, this protein subassembly forms the "core" of the secretion apparatus.; The second Dot/Icm protein subassembly contains the type IV coupling protein DotL, the inner membrane proteins DotM and DotN, and the cytoplasmic proteins IcMS, IcmW, and LvgA. As the type IV coupling protein, DotL has been proposed to function as the inner membrane receptor for secreted substrates. Our findings support this model, as we have shown a direct interaction between DotL and two components of the secretion apparatus, DotM and DotN, as well as with the cytoplasmic adaptor proteins IcmS, IcmW, and LvgA, which are thought to function similarly to type III secretion chaperones. These finding suggest a molecular mechanism for substrate delivery to the secretion machinery, whereby interactions between substrates and the secretion apparatus are mediated by interactions between the adaptor proteins and the coupling protein DotL.