The ergothioneine transporter (ETT): substrates and locations, an inventory

Abstract

In all vertebrates including mammals, the ergothioneine transporter ETT (obsolete name OCTN1; human gene symbol SLC22A4) is a powerful and highly specific transporter for the uptake of ergothioneine (ET). ETT is not expressed ubiquitously and only cells with high ETT cell‐surface levels can accumulate ET to high concentration. Without ETT, there is no uptake because the plasma membrane is essentially impermeable to this hydrophilic zwitterion. Here, we review the substrate specificity and localization of ETT, which is prominently expressed in neutrophils, monocytes/macrophages, and developing erythrocytes. Most sites of strong expression are conserved across species, but there are also major differences. In particular, we critically analyze the evidence for the expression of ETT in the brain as well as recent data suggesting that the transporter SLC22A15 may also transport ET. We conclude that, to date, ETT remains the only well‐defined biomarker for intracellular ET activity. In humans, the ability to take up, distribute, and retain ET depends principally on this transporter.

Discovery and structure of a widespread bacterial ABC transporter specific for ergothioneine

“…In this case, ET is likely obtained in the diet of the vertebrate host where GI-resident bacteria that express EgtUV would have initial access to this metabolite. As described above, the human ET transporter (ETT) is expressed in a wide range of tissues and cells, including neutrophils and macrophages 48 ; this suggests that ET may be bioavailable to both extracellular and intracellular pathogens, e . g ., those phagocytosed by neutrophils.…”

“…In this case, ET is likely obtained in the diet of the vertebrate host where GI-resident bacteria that express EgtUV would have initial access to this metabolite. As described above, the human ET transporter (ETT) is expressed in a wide range of tissues and cells, including neutrophils and macrophages 48 ; this suggests that ET may be bioavailable to both extracellular and intracellular pathogens, e.g., those phagocytosed by neutrophils. This is not yet known with certainty since concentrations of ET itself have not been comprehensively mapped in a wide variety of tissues or cells in an infected host using the analytical approaches we describe here.…”

“…These studies suggest that ET is significantly bioavailable in vertebrates and could be exploited by both resident commensals and pathogenic organisms to provide protection against host oxidative insults; however, no widespread bacterial transporter for ET is known 36,47,48 . Here, we describe the discovery and structural characterization of a bacterial ET transporter.…”

Ergothioneine, where are we now?

“…The specificity of ETT for ET has often been challenged but has been reconfirmed in several studies [11–13], as reviewed in depth by Grundemann et al . in this special issue [14]. The presence of a specific transporter together with the avid retention of ET in the body implies that this compound is important to us, and indeed in 2018 Bruce Ames proposed that ET be classified as a ‘longevity vitamin’ [15].…”

“…One catalyst for this upsurge of interest was the discovery in 2005 of a transporter for ET (OCTN1, often now called the ergothioneine transporter, ETT), which accounts for the fact that animals (including humans) take up and avidly retain ET from the diet [11]. The specificity of ETT for ET has often been challenged but has been reconfirmed in several studies [11][12][13], as reviewed in depth by Grundemann et al in this special issue [14]. The presence of a specific transporter together with the avid retention of ET in the body implies that this compound is important to us, and indeed in 2018 Bruce Ames proposed that ET be classified as a 'longevity vitamin' [15].…”