Zinc is an essential nutrient—it is stored during periods of excess to promote detoxification and released during periods of deficiency to sustain function. Lysosome-related organelles (LROs) are an evolutionarily conserved site of zinc storage, but mechanisms that control the directional zinc flow necessary for homeostasis are not well understood. In Caenorhabditis elegans intestinal cells, the CDF-2 transporter stores zinc in LROs during excess. Here, we identify ZIPT-2.3 as the transporter that releases zinc during deficiency; ZIPT-2.3 transports zinc, localizes to the membrane of LROs in intestinal cells, and is necessary for zinc release from LROs and survival during zinc deficiency. In zinc excess and deficiency, the expression levels of CDF-2 and ZIPT-2.3 are reciprocally regulated at the level of mRNA and protein, establishing a fundamental mechanism for directional flow to promote homeostasis. To elucidate how the ratio of CDF-2 and ZIPT-2.3 is altered, we used super-resolution microscopy to demonstrate that LROs are composed of a spherical acidified compartment and a hemispherical expansion compartment. The expansion compartment increases in volume during zinc excess and deficiency. These results identify the expansion compartment as an unexpected structural feature of LROs that facilitates rapid transitions in the composition of zinc transporters to mediate homeostasis, likely minimizing the disturbance to the acidified compartment.

Orsay virus is the only known natural virus pathogen of Caenorhabditis elegans , which shares many evolutionarily conserved pathways with humans. We leveraged the powerful genetic tractability of C. elegans to characterize a novel interaction between zinc, lipids, and virus infection.

Zinc is an essential element that plays many roles in animals. Since excess zinc is toxic, animals have evolved sophisticated mechanisms to achieve homeostasis. A conserved mechanism is to store excess zinc in specialized lysosomes, which contributes to zinc detoxification and provides a supply when zinc becomes limiting. In C. elegans excess zinc conditions promote an increase in lysosome-related organelles called bilobed granules. Defining how zinc-regulated transcription drives the observed lysosome remodeling is key to understanding zinc homeostasis processes. Here we describe a positively regulated zinc cascade controlled by hizr-1 and hlh-30/TFEB , which encode the C. elegans high zinc sensor and the master regulator of the autophagy-lysosomal pathway, respectively; essential for connecting excess zinc homeostasis to lysosome biogenesis and remodeling. Our transcriptomic, genetic, and bioinformatic studies indicate that hizr-1 and hlh-30 are necessary and sufficient to activate transcription of lysosome genes under excess zinc conditions. In our regulatory model, zinc binding activates HIZR-1 protein, which accumulates in the nucleus and activates genes containing the HZA enhancer, including hlh-30 . HLH-30 protein accumulates in the nucleus and activates genes containing the E-box enhancer. Genetic analysis of loss-of-function mutants demonstrated that both hizr-1 and hlh-30 are necessary for animals to tolerate excess zinc. Furthermore, HLH-30 promotes the increase in the number of acidified compartments, whereas HIZR-1 promotes the increase in the volume of the expansion compartment. These results define a genetic pathway that responds to excess zinc by increasing the number of lysosome-related organelles and their capacity to store and detoxify cytosolic zinc.

Antibiotic-, biocide-, and metal-resistance genes co-occur in the genomes of multidrug-resistant bacteria. This relationship is more complex than mere physical co-localization. Instead, it arises from co-selection pressures that favor co-regulation and co-resistance. The genomic basis of this co-occurrence remains unclear. We predicted the co-occurrence of Cu(I)-ATPases with other metal-extrusion systems in Methylobacterium extorquens. In this study, we identified a more complex co-occurrence of Cu(I)-ATPases in the pathogen Brucella anthropi ATCC 49188. It comprises five collinear gene clusters spanning 48.5 kb and may be involved in multimetal homeostasis, redox homeostasis, conjugation, and the transport of miscellaneous molecules. We found highly homologous clusters in 43 strains across 3 alpha-proteobacterial orders, isolated from diverse habitats in different countries. Despite these geographical differences and phylogenetic distances, most orthologous genes remain syntenic. We called this gene arrangement a Collinear Synteny Block (CSB). In 20 species, these CSBs reside within an inferred ~110 kb genomic island, which may have contributed to their dispersion. CSBs co-occur with potential antibiotic-resistance genes scattered across the same replicon. This study will advance our understanding of the organization, evolution, and dispersal of resistance genes in bacteria. This genome-mining study is entirely predictive, and the proposed hypothesis requires experimental validation.

Antibiotic-, biocide-, and metal-resistance genes co-occur in the genomes of multidrug-resistant bacteria. This relationship is more complex than mere physical co-localization. Instead, it arises from co-selection pressures that favor co-regulation and co-resistance. The genomic basis of this co-occurrence remains unclear. Our studies on the co-occurrence of Cu(I)-ATPases with other metal-extrusion systems in the Methylobacterium extorquens AM1 genome revealed 3 Multimetal Homeostasis Gene Clusters (MHGCs) presumed to confer resistance to Cu/Ni/Co/Zn/Cd/Pb. In this study, we identified a more complex co-occurrence of Cu(I)-ATPases in the pathogen Brucella anthropi ATCC 49188. It comprises five collinear gene clusters (CGCs) spanning 48.5 kb and involved in multimetal and redox homeostasis, conjugation, and the transport of miscellaneous molecules. Highly homologous clusters were found in 43 strains across 3 alpha-proteobacterial orders, isolated from diverse habitats in different countries. Despite these geographical differences and phylogenetic distances, most orthologous genes remain syntenic. This arrangement of genes was named a Collinear Synteny Block (CSB). In some species, these CSBs reside within a ~110-kb genomic island, which explains their widespread occurrence. The CSB co-occurs with potential antibiotic-resistant genes scattered across the same replicon. This study will advance our understanding of the organization, evolution, and dispersal of resistance genes in bacteria.