Guang Yang’s research while affiliated with University of Florida and other places

As an ancient cellular co-factor ubiquitously present in all domains of life, nearly all iron-sulfur ([Fe-S]) clusters are assembled in the mitochondrion. Although multiple mitochondrion-derived signalings are known to be key players in longevity regulation, whether the mitochondrial [Fe-S] cluster assembly machinery modulates lifespan is previously unknown. Here, we find that ISCU-1, the C. elegans ortholog of the evolutionarily conserved iron-sulfur cluster (ISC) assembly machinery central protein ISCU, regulates longevity and stress response. Specifically, ISCU-1 accelerates aging in the intestine. Moreover, we identify the Nrf2 transcription factor SKN-1 and a nuclear hormone receptor NHR-49 as the downstream factors of ISCU-1. Lastly, a mitochondrial outer membrane protein phosphatase PGAM-5 appears to link ISCU-1 to SKN-1 and NHR-49 in lifespan regulation. Together, we have identified a novel function of mitochondrial ISC assembly machinery in longevity modulation and stress response.

As an ancient cellular co-factor ubiquitously present in all domains of life, nearly all iron-sulfur ([Fe-S]) clusters are assembled in the mitochondrion. Although multiple mitochondria-derived signalings are known to be key players in longevity regulation, whether the mitochondrial [Fe-S] cluster assembly machinery modulates lifespan is previously unknown. Here, we find that ISCU-1, the C. elegans ortholog of the evolutionarily conserved iron-sulfur cluster (ISC) assembly machinery central protein ISCU, regulates longevity and stress response. Specifically, ISCU-1 accelerates aging in the intestine. Moreover, we identify the Nrf2 transcription factor SKN-1 and a nuclear hormone receptor NHR-49 as the downstream factors of ISCU-1. Lastly, a mitochondrial outer membrane protein phosphatase PGAM-5 appears to link ISCU-1 to SKN-1 and NHR-49 in lifespan regulation. Together, we have identified a novel function of mitochondrial ISC assembly machinery in longevity modulation and stress response.

All living organisms are subject to the continuously changing environmental stimuli from various sources. Neurosensory systems perceive these cues and elicit appropriate physiological responses. Although sensory perception is traditionally considered as an acute response, recent studies in model organisms have demonstrated that it can also have a long-term effect on aging. Using evolutionarily conserved signaling pathways such as insulin/IGF-1 signaling and nuclear hormone receptor signaling, neurosensory systems can transduce ambient cues into longevity signals. In this chapter, we review recent studies implicating sensory neurons and signaling pathways in longevity modulation. As model organisms including Caenorhabditis elegans and Drosophila feature short lifespan and facile genetics, many mechanistic studies of neurosensory modulation of aging were initially conducted in these organisms. Given the evolutionary conservation of genes and signaling pathways involved in sensory perception and aging, findings from model organisms will shed light on the broad impact of neurosensory systems on aging.

Proteotoxic stress is a common challenge for all organisms. Among various mechanisms involved in defending such stress, the evolutionarily conserved unfolded protein responses (UPRs) play a key role across species. Interestingly, UPRs can occur in different subcellular compartments including the endoplasmic reticulum (UPRER), mitochondria (UPRMITO), and cytoplasm (UPRCYTO) through distinct mechanisms. While previous studies have shown that the UPRs are intuitively linked to organismal aging, a systematic assay on the temporal regulation of different type of UPRs during aging is still lacking. Here, using Caenorhabditis elegans (C. elegans) as the model system, we found that the endogenous UPRs (UPRER, UPRMITO, and UPRCYTO) elevate with age, but their inducibility exhibits an age‐dependent decline. Moreover, we revealed that the temporal requirements to induce different types of UPRs are distinct. Namely, while the UPRMITO can only be induced during the larval stage, the UPRER can be induced until early adulthood and the inducibility of UPRCYTO is well maintained until mid‐late stage of life. Furthermore, we showed that different tissues may exhibit distinct temporal profiles of UPR inducibility during aging. Collectively, our findings demonstrate that UPRs of different subcellular compartments may have distinct temporal mechanisms during aging.

Some fungal epithiodiketopiperazine alkaloids display α,β‐polysulfide bridges alongside diverse structural variations. However, the logic of their chemical diversity has rarely been explored. Here, we report the identification of three new (2, 3, 8) and five known (1, 4–7) epithiodiketopiperazines of this subtype from a marine‐derived Penicillium sp. The structure elucidation was supported by multiple spectroscopic analyses. Importantly, we observed multiple nonenzymatic interconversions of these analogues in aqueous solutions and organic solvents. Furthermore, the same biosynthetic origin of these compounds was supported by one mined gene cluster. The dominant analogue (1) demonstrated selective cytotoxicity to androgen‐sensitive prostate cancer cells and HIF‐depleted colorectal cells and mild antiaging activities, linking the bioactivity to oxidative stress. These results provide crucial insight into the formation of fungal epithiodiketopiperazines through chemical interconversions.

Microbes are essential to the global ecosystem but undesirable microbial growth causes issues ranging from food spoilage and infectious diseases to harmful cyanobacterial blooms. The use of chemicals to control microbial growth has achieved significant successes, while specific roles for a majority of essential genes in growth control remain unexplored. Here, we show the growth inhibition of cyanobacterial species by targeting an essential enzyme for the biosynthesis of branched-chain amino acids. Specifically, we report the biochemical, genetic, and structural characterization of dihydroxyacid dehydratase from the model cyanobacterium Synechocystis sp. PCC 6803 (SnDHAD). Our studies suggest that SnDHAD is an oxygen-stable enzyme containing a [2Fe-2S] cluster. Furthermore, we demonstrate that SnDHAD is selectively inhibited in vitro and in vivo by the natural product aspterric acid, which also inhibits the growth of representative bloom-forming Microcystis and Anabaena strains but has minimal effects on microbial pathogens with [4Fe-4S] containing DHADs. This study suggests DHADs as a promising target for the precise growth control of microbes and highlights the exploration of other untargeted essential genes for microbial management.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an important family of natural products. Their biosynthesis follows a common scheme in which the leader peptide of a precursor peptide guides the modifications of a single core peptide. Here we describe biochemical studies of the processing of multiple core peptides within a precursor peptide, rare in RiPP biosynthesis. In a cyanobacterial microviridin pathway, an ATP-grasp ligase, AMdnC, installs up to two macrolactones on each of the three core peptides within AMdnA. The enzyme catalysis occurs in a distributive fashion and follows an unstrict N-to-C overall directionality, but a strict order in macrolactonizing each core peptide. Furthermore, AMdnC is catalytically versatile to process unnatural substrates carrying one to four core peptides, and kinetic studies provide insights into its catalytic properties. Collectively, our results reveal a distinct biosynthetic logic of RiPPs, opening up the possibility of modular production via synthetic biology approaches.

Mycosporine-like amino acids (MAAs) are secondary metabolites of a variety of marine organisms including cyanobacteria and macroalgae. These compounds have strong ultraviolet (UV) absorption maxima between 310 and 362 nm and are biological sunscreens for counteracting the damaging effects of UV radiation in nature. The common MAA shinorine has been used as one key active ingredient of environmentally friendly sunscreen creams. Commercially used shinorine is isolated from one red algae that is generally harvested from the wild. Here, we describe the use of Synechocystis sp. PCC6803 as a host for the heterologous production of shinorine. We mined a shinorine gene cluster from the filamentous cyanobacterium Fischerella sp. PCC9339. When expressing the cluster in Synechocystis sp. PCC6803, we observed the production of shinorine using LC-MS analysis but its productivity was three times lower than the native producer. Integrated transcriptional and metabolic profiling identified rate-limiting steps in the heterologous production of shinorine. The use of multiple promoters led to a 10-fold increase of its yield to 2.37 ± 0.21 mg/g dry biomass weight, comparable to commercially used shinorine producer. The UV protection of shinorine was further confirmed using the engineered Synechocystis sp. PCC6803. This work was the first time to demonstrate the photosynthetic over-production of MAA. The results suggest that Synechocystis sp. PCC6803 can have broad applications as the synthetic biology chassis to produce other cyanobacterial natural products, expediting the translation of genomes into chemicals.