Endogenous and Borrowed Proteolytic Activity in the Borrelia

Abstract

The Borrelia spp. are tick-borne pathogenic spirochetes that include the agents of Lyme disease and relapsing fever. As part of their life cycle, the spirochetes traffic between the tick vector and the vertebrate host, which requires significant physiological changes and remodeling of their outer membranes and proteome. This crucial proteome resculpting is carried out by a diverse set of proteases, adaptor proteins, and related chaperones. Despite its small genome, Borrelia burgdorferi has dedicated a large percentage of its genome to proteolysis, including a full complement of ATP-dependent proteases. Energy-driven proteolysis appears to be an important physiological feature of this dual-life-cycle bacterium. The proteolytic arsenal of Borrelia is strategically deployed for disposal of proteins no longer required as they move from one stage to another or are transferred from one host to another. Likewise, the Borrelia spp. are systemic organisms that need to break down and move through host tissues and barriers, and so their unique proteolytic resources, both endogenous and borrowed, make movement more feasible. Both the Lyme disease and relapsing fever Borrelia spp. bind plasminogen as well as numerous components of the mammalian plasminogen-activating system. This recruitment capacity endows the spirochetes with a borrowed proteolytic competency that can lead to increased invasiveness.

Keywords: Borrelia; borrowed proteolysis; plasminogen; proteases; proteolytic enzymes.

FIG 1

Architectural arrangements of AAA+ proteases. (Left) The structural model of Lon protease hexamer in the active substrate-engaged state is shown (PDB 6ON2). Each Lon monomer contains both the ATPase and the peptidase domains. In this depiction, one of the six Lon protomers is omitted to highlight the bound substrate (yellow), staircase arrangement of the active substrate engaged enzyme, and the peptidase active-site Ser-Lys dyad (purple). (Right) The structural model of the ClpAP protease in the active substrate-engaged state is shown (PDB 6W1Z). The ClpA ATPase forms a homohexamer that sets on top of the assembled ClpP peptidase, which is composed of two stacked heptamers (dark red and red, respectively). In this depiction, one of the six ClpA protomers is omitted to highlight the two AAA+ domains and the bound substrate (yellow).

FIG 2

Architectural arrangements of HtrA and DegP proteases. (Left) The structural model of HtrA protease trimer in the active peptide-bound state is shown (PDB 2Z9I). Each HtrA monomer is shown in a different color, with two monomers containing a bound autoproteolytic peptide (yellow) to the active site. The third monomer is shown without the bound peptide to highlight the active-site Ser-His-Glu catalytic triad (red). (Right) A structural model of the DegP protease dodecamer in the substrate-bound state (PDB 4A8D) is shown. The DegP chaperone forms a cage-like structure composed of 4 trimers, each depicted in a different color, with the bound substrate (outer membrane protein [OMP]; yellow) captured inside the dodecameric cage.

FIG 3

Mammalian plasminogen activation system indicating all of its components that interact with Borrelia species.

FIG 4

A schematic overview of the key endogenous and borrowed proteases Borrelia spp. use to remodel their proteomes as they move from one stage, tissue, or host to another. Major cytoplasmic and inner membrane proteases, Lon, ClpAP (as a representative of the Clp protease systems ClpXP, ClpYQ, and ClpCP), and FtsH are shown. There are bound substrates highlighted in red. The lone periplasmic protease HtrA, which is also secreted, is shown in the periplasmic space and associated with the cell surface. The yellow ovals represent cholesterol-rich lipid rafts, which are of functional importance and exist in both the inner and outer membranes of Borrelia. The borrowed plasmin proteolytic system is shown bound to Borrelia outer surface proteins (Osp), and additional cell surface receptors, shown as a green oval. The 5 kringle domains of plasmin are colored purple, and its protease domain is light green. The periplasmic flagella are not shown.