A More Flexible Lipoprotein Sorting Pathway

Abstract

Lipoprotein biogenesis in Gram-negative bacteria occurs by a conserved pathway, each step of which is considered essential. In contrast to this model, LoVullo and colleagues demonstrate that the N-acyl transferase Lnt is not required in Francisella tularensis or Neisseria gonorrhoeae. This suggests the existence of a more flexible lipoprotein pathway, likely due to a modified Lol transporter complex, and raises the possibility that pathogens may regulate lipoprotein processing to modulate interactions with the host. Lipoproteins are a diverse class of multifunctional, membraneassociated molecules. Their contributions to the bacterial cell range from essential processes, such as maintaining envelope architecture and stability, to assisting with and mediating hostpathogen interactions (1-3). Lipoproteins constitute a significant fraction of the outer membrane (OM) of Gram-negative bacteria and are recognized as a pathogen-associated molecular pattern by host cells (3,4). Due to the high cost associated with lipoprotein mislocalization, Gram-negative bacteria have evolved a conserved mechanism for the processing and sorting of these molecules, to ensure they correctly reach their final destination. In this issue of the Journal of Bacteriology, LoVullo et al. (5) challenge the current paradigm for lipoprotein processing and sorting in Gram-negative bacteria.As with the majority of proteins destined for the periplasm or OM, the N terminus of a newly synthesized lipoprotein contains a cleavable signal peptide, which typically directs the preprolipoprotein to the Sec general secretory pathway for translocation across the cytoplasmic or inner membrane (IM) to the periplasm ( Fig. 1) (2, 6). The C-terminal end of the signal peptide contains a 4-amino-acid lipobox motif, terminating with an invariant cysteine in the ϩ1 position (the N terminus of the mature lipoprotein). This cysteine provides the acylation site and is required for lipoprotein processing. In addition, residues in the ϩ2, ϩ3, and ϩ4 positions adjacent to the lipobox cysteine act as signals that determine whether the lipoprotein is sorted to the OM (the default pathway) or remains in the IM (7,8). Finally, a flexible tethering sequence links the N-terminal processing and sorting determinants to the mature functional region of the protein (2).Following transport through the Sec translocon to the periplasm, the preprolipoprotein remains anchored to the IM by its N-terminal signal peptide (Fig. 1). Lgt, a preprolipoprotein diacylglyceryl transferase, catalyzes the addition of a diacylglyceride moiety to the sulfhydryl group of the ϩ1 cysteine, forming a prolipoprotein (9). Next, the prolipoprotein signal peptidase Lsp cleaves the Nterminal amide bond of the ϩ1 cysteine, releasing the signal peptide and leaving the lipoprotein anchored to the IM via its diacylated cysteine residue (10). With the ϩ1 cysteine amino group now accessible, the final processing step requires the N-acyl transferase Lnt to catalyze the linkage of an additional acyl chain to the free am...

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