Bacterial Moonlighting Proteins That Act as Invasins

Bacterial invasion of nonphagocytic cells is dependent on the interaction of specific bacterial proteins (invasins) with host cell-surface receptors, or may be through the injection of cell modulators to alter host cell function (Pizarro-Cerda and Cossart 2006). Only a small number of bacterial moonlighting proteins have been demonstrated to function as invasins. These include Strep. pyogenes GAPDH, which binds to uPAR/CD87 to enable cell entry (Jin et al. 2005), the chaperonin 60 protein of Legionella pneumophila (Chong et al. 2009; see also Chapter 6), and a range of peptidyl prolyl isomerases (Norville et al. 2011; Rasch et al. 2014; see also Chapter 7). Many of the receptors for these moonlighting invasins are themselves moonlighting proteins (e.g., uPAR/CD87) and this will be discussed in more detail in Section 3.5.

Bacterial Moonlighting Proteins Involved in Nutrient Acquisition

Bacterial invasion into the human body would be thought to be like a starving man arriving at a feast. All the nutrients that the bacterium needed would be available from the host. Nutrient acquisition is essential for bacterial growth and is therefore an evolutionary target for antibacterial defense. The best-known example of this is the essential metal, iron. While the average human has 4-5 g of iron in their bodies, the level of the free metal in human biological fluids is kept extremely low through its binding to two high-affinity iron-binding proteins: transferrin and lactoferrin (Skaar 2010). This nutritional defense mechanism has been countered by the evolution, by bacteria, of proteins that bind host ironbinding proteins (transferrin, lactoferrin, hemoglobin, haptoglobin, etc.), heme, and also small organic molecules termed siderophores which bind directly to free iron (Morgenthau et al. 2013). For example, the Neisseria, which do not manufacture siderophores, utilize two transferrin-binding proteins (A and B) to take up iron (Noinaj et al. 2012).

When we turn to moonlighting proteins and iron binding, the first such report was of the GAPDH of Staphylococcus aureus acting as a transferrin receptor (Modun and Williams 1999). This finding was not confirmed by Taylor and Heinrichs (2002) and an explanation for this may be that Staph. aureus has two genes encoding GAPDH. In one study, only the glyceraldehyde 3-phosphate dehydrogenase protein known as GapC was found to contribute to bacterial pathogenicity (Kerro-Dego et al. 2012); this difference in the literature could be due to the two groups employing different GAPDHs. Since these early studies, the GADPH of Streptococcus suis (a pig pathogen) has been shown to function as a heme-binding protein (Hannibal et al. 2012) and, as explained in Chapter 11, the Mycobacterium tuberculosis GAPDH functions as a transferrin-binding protein (Boradia et al. 2014). In addition, the peroxiredoxin of Strep. agalactiae functions as a heme-binding protein (Lechardeur et al. 2011) and certain of the porins of enteropathogens function as transferrin-binding protein (Sandrini et al. 2013). Moonlighting proteins therefore appear to contribute to the ability of bacteria to capture iron. To show the unexpected nature of protein moonlighting, it has recently been reported that the Staph. aureus manganese transport protein, MntC, binds plasminogen and extracellular matrix proteins (Salazar et al. 2014).

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