Abstract
Proteins containing DUF59 domains have roles in iron-sulfur (FeS) cluster assembly and are widespread throughout Eukarya, Bacteria, and Archaea. However, the function(s) of this domain is unknown. Staphylococcus aureus SufT is composed solely of a DUF59 domain. We noted that sufT is often co-localized with sufBC, which encode for the Suf FeS cluster biosynthetic machinery. Phylogenetic analyses indicated that sufT was recruited to the suf operon, suggesting a role for SufT in FeS cluster assembly. A S. aureus ΔsufT mutant was defective in the assembly of FeS proteins. The DUF59 protein Rv1466 from Mycobacterium tuberculosis partially corrected the phenotypes of a ΔsufT mutant, consistent with a widespread role for DUF59 in FeS protein maturation. SufT was dispensable for FeS protein maturation during conditions that imposed a low cellular demand for FeS cluster assembly. In contrast, the role of SufT was maximal during conditions imposing a high demand for FeS cluster assembly. SufT was not involved in the repair of FeS clusters damaged by reactive oxygen species or in the physical protection of FeS clusters from oxidants. Nfu is a FeS cluster carrier and nfu displayed synergy with sufT. Furthermore, introduction of nfu upon a multicopy plasmid partially corrected the phenotypes of the ΔsufT mutant. Biofilm formation and exoprotein production are critical for S. aureus pathogenesis and vancomycin is a drug of last-resort to treat staphylococcal infections. Defective FeS protein maturation resulted in increased biofilm formation, decreased production of exoproteins, increased resistance to vancomycin, and the appearance of phenotypes consistent with vancomycin-intermediate resistant S. aureus. We propose that SufT, and by extension the DUF59 domain, is an accessory factor that functions in the maturation of FeS proteins. In S. aureus, the involvement of SufT is maximal during conditions of high demand for FeS proteins.
Highlights
Iron (Fe) is an essential nutrient for most organisms
Proteins containing DUF59 domains are widespread in Eukarya, Bacteria, and Archaea
In this report we show SufT to be an accessory factor utilized in FeS cluster assembly during conditions imposing a high-demand for FeS proteins
Summary
Iron (Fe) is an essential nutrient for most organisms. Fe is acquired from the environment and is transported into cells using specific uptake systems. Studies have shown that ~80% of the intracellular Fe is located in inorganic cofactors, called iron-sulfur (FeS) clusters, and heme in a respiring microorganism [1]. The metabolisms of most organisms are highly reliant on FeS cluster chemistry and a failure to properly assemble FeS clusters in proteins can result in widespread metabolic disorders, metabolic paralysis, and cell death [2,3,4]. FeS proteins function in diverse metabolic processes including environmental sensing[5], carbon transformations [6], DNA repair and replication [7,8], RNA metabolism [9], protein synthesis [10], nucleotide, vitamin, and cofactor synthesis [11,12,13], and cellular respiration [14,15,16]. FeS clusters are typically found in proteins as [Fe2S2] or [Fe4S4] clusters, but the use of complex FeS clusters has evolved for processes such as dinitrogen [17], carbon monoxide [18], and hydrogen metabolism [19]
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