Introduction to the 9th International Biometals Webinars, Clostridioides difficile activates an anticipatory iron storage strategy in response to nutritional immunity, Iron-sulfur protein biogenesis in eukaryotes: How all starts

Abstract

Introduction to the 9th International Biometals WebinarsIntroduce speakersClostridioides difficile activates an anticipatory iron storage strategy in response to nutritional immunityAll cells require nutrient metal to carry out essential biochemical processes. This requirement is something that the vertebrate immune system has exploited as a strategy to defend against infection by restricting microbial access to nutrient metal. This process of nutrient restriction during infection is called “nutritional immunity”. Bacterial pathogens have evolved elaborate mechanisms to circumvent nutritional immunity and acquire metal during infection. This struggle for nutrient metal impacts both microbial virulence as well as the immune response of the host, profoundly affecting the outcome of host-pathogen interactions. Nutrient metals are acquired through the diet, establishing the gastrointestinal tract as a primary battleground in the struggle for metal between microbes and the vertebrate host. Clostridioides difficile is the leading cause of hospital acquired gastrointestinal infections, and this organism must compete with both the host and other microbes to obtain the critical nutrients that it needs to colonize and cause disease. To study these interactions in more detail, we have combined microbial genetics with murine models of infection and advanced imaging modalities. We have applied this platform to the study of C. difficile infection, leading to the discovery of infection-associated alterations in the distribution and abundance of nutrients in tissue. These data have led to the discovery of C. difficile factors that are required to acquire and metabolize nutrients and have led to unexpected findings regarding how nutrient metals and antibiotic resistance intersect in this organism.Iron-sulfur protein biogenesis in eukaryotes: How all startsIron-sulfur (Fe-S) proteins play crucial roles in numerous important cellular processes including respiration, metabolism, genome maintenance, protein translation and antiviral response. The synthesis of Fe S clusters and their insertion into apoproteins in (non-green) eukaryotes is a multifaceted process involving over 30 proteins located in mitochondria and cytosol. The biogenesis of mitochondrial [2Fe-2S] and [4Fe-4S] proteins is orchestrated by components of the iron-sulfur cluster assembly (ISC) machinery which was inherited from bacteria during evolution (Braymer et al., 2017; Lill Freibert, 2020; Lill, 2020). Cytosolic and nuclear Fe-S protein assembly also relies on the function of this machinery, yet additionally requires the mitochondrial ABC exporter ABCB7 and the cytosolic iron-sulfur protein assembly (CIA) machinery (Paul et al., 2015). Interestingly, mitochondrial Fe-S protein biogenesis co-evolved with the existence of the entire organelle, defining this process as both the minimal and essential function of mitochondria (Braymer et al., 2021). A combination of in vivo and in vitro studies have generated a good understanding of the general outline of the sequential steps of Fe-S protein biogenesis. Currently, the detailed molecular mechanisms underlying the individual reaction steps are investigated by using cell biological, biochemical, spectroscopic, and structural approaches. In this seminar, I will present some of our recent structural, spectroscopic, and biochemical insights into the molecular mechanisms underlying [2Fe-2S] cluster assembly in mitochondria. The mechanism may closely resemble that in the bacterial ISC system. These mechanistic insights may eventually help advancing our molecular understanding of the biochemical consequences of numerous “Fe-S diseases” linked to mutations in almost any of the ISC genes (Lill Freibert, 2020). Specifically, our studies suggest a mechanism for frataxin function, a protein functionally impaired in Friedreich’s ataxia.