The Great Escape: Protein Trafficking from the Bacterial Cytosol to the Outer Membrane

To protect their delicate, carefully curated contents from the world, bacteria encase themselves within a protective envelope made up of sugars, lipids, and proteins. Cell envelopes give bacteria their characteristic shapes, provide rigidity and mechanical stability, and form a selective antechamber—granting access only to a desirable subset of environmental substances. Yet this protective layer is a double-edged sword: Its effectiveness at keeping things out also makes it difficult for things to leave, including the proteins required to interface with the outside world and form the envelope itself. Bacteria have solved this problem by constructing an array of proteinaceous nanomachines that expend energy to selectively shuttle proteins and other building blocks to their intended destinations. Here, we present an overview of our current understanding of how these transporters work, focusing on the major, conserved machines that ferry proteins across the cell envelope throughout the domain Bacteria. The emphasis is on recent discoveries and open questions, with the hope that answering these will provide new avenues to help combat the rising threat of antimicrobial resistance and the rapidly expanding list of diseases linked to human microbiome composition.