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Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits prolyl hydroxylase 3 (PHD3) to pyruvate kinase 2 (PKM2) to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with heterogeneous nuclear ribonucleoprotein F (hnRNPF) to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly reduces their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment. HIF1alpha is reported to drive tumourigenesis through activating glycolysis. Here, the authors show that HIFAL, the HIF1alpha antisense long non-coding RNA, and HIF1alpha form a positive feed-forward loop which is essential for HIF1a-mediated metabolic reprogramming and oncogenic role.

C. neoformans is the main causative agent of fungal meningitis that is responsible for about 15% of all HIV-related deaths. Although an obligate aerobic fungus, C. neoformans is well adapted to hypoxia conditions that the fungus could encounter in the host or the environment. To aerobic organisms, low oxygen tension (hypoxia) presents a physiological challenge. To cope with such a challenge, metabolic pathways such as those used in energy production have to be adjusted. Many of such metabolic changes are orchestrated by the conserved hypoxia-inducible factors (HIFs) in higher eukaryotes. However, there are no HIF homologs in fungi or protists, and not much is known about conductors that direct hypoxic adaptation in lower eukaryotes. Here, we discovered that the transcription factor Pas2 controls the transcript levels of metabolic genes and consequently rewires metabolism for hypoxia adaptation in the human fungal pathogen Cryptococcus neoformans . Through genetic, proteomic, and biochemical analyses, we demonstrated that Pas2 directly interacts with another transcription factor, Rds2, in regulating cryptococcal hypoxic adaptation. The Pas2/Rds2 complex represents the key transcription regulator of metabolic flexibility. Its regulation of metabolism rewiring between respiration and fermentation is critical to our understanding of the cryptococcal response to low levels of oxygen. IMPORTANCE C. neoformans is the main causative agent of fungal meningitis that is responsible for about 15% of all HIV-related deaths. Although an obligate aerobic fungus, C. neoformans is well adapted to hypoxia conditions that the fungus could encounter in the host or the environment. The sterol regulatory element binding protein (SREBP) is well known for its role in cryptococcal adaptation to hypoxia through its regulation of ergosterol and lipid biosynthesis. The regulation of metabolic reprogramming under hypoxia, however, is largely unknown. Here, we discovered one key regulator, Pas2, that mediates the metabolic response to hypoxia together with another transcription factor, Rds2, in C. neoformans . The findings help define the molecular mechanisms underpinning hypoxia adaptation in this and other lower eukaryotes.

Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer. Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.

Vaccination is one of the most effective public health measures for preventing and managing infectious diseases. Despite intensive efforts from the relatively small medical mycology community, developing effective vaccines against invasive fungal infections remains a scientific challenge. This is predominantly due to large antigenic repertoires, complicated life cycles, and the capacity of fungal pathogens to evade the host immune system. Additionally, antifungal vaccines often need to work for at-risk individuals who are immunodeficient. We anticipate that the success of mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its exploration for various infectious diseases and cancers will usher a new wave of antifungal vaccine research. Herein, we discuss recent advancements and key scientific areas that need to be explored to actualize the development of effective antifungal mRNA vaccines.

Cryptococcus neoformans is a ubiquitous human fungal pathogen. This pathogen can undergo morphotype transition between the yeast and the filamentous form and such morphological transition has been implicated in virulence for decades. Morphotype transition is typically observed during mating, which is governed by pheromone signaling. Paradoxically, components specific to the pheromone signaling pathways play no or minimal direct roles in virulence. Thus, the link between morphotype transition and virulence and the underlying molecular mechanism remain elusive. Here, we demonstrate that filamentation can occur independent of pheromone signaling and mating, and both mating-dependent and mating-independent morphotype transition require the transcription factor Znf2. High expression of Znf2 is necessary and sufficient to initiate and maintain sex-independent filamentous growth under host-relevant conditions in vitro and during infection. Importantly, ZNF2 overexpression abolishes fungal virulence in murine models of cryptococcosis. Thus, Znf2 bridges the sex-independent morphotype transition and fungal pathogenicity. The impacts of Znf2 on morphological switch and pathogenicity are at least partly mediated through its effects on cell adhesion property. Cfl1, a Znf2 downstream factor, regulates morphogenesis, cell adhesion, biofilm formation, and virulence. Cfl1 is the first adhesin discovered in the phylum Basidiomycota of the Kingdom Fungi. Together with previous findings in other eukaryotic pathogens, our findings support a convergent evolution of plasticity in morphology and its impact on cell adhesion as a critical adaptive trait for pathogenesis.

The existence of morphotype-associated pathogenicity is also observed in some zygomycetes [10] and in dermatophytes [11]. [...]it appears that pathogens of different major phyla in the fungal kingdom have adopted dimorphism as a common pathogenic strategy. [...]the znf2δ mutant is more virulent than the wild type, even though both strains are in the yeast form during infection [8], [9]. Success by these fungi to colonize the host, establish infections, and disseminate systemically is a combination of the downregulation of filament- or spore-specific molecules and upregulation of the yeast-specific ones. [...]investigation of cell-surface molecules specific to each morphological form will provide a new opportunity to comprehend host-fungus interactions.

Vaccines are one of the most effective public health tools to prevent and manage infectious diseases. Since the first clinical use of vaccines in the late 18th century, many vaccines have been successfully developed to combat bacterial and viral infections, including the most recent Coronavirus Disease 2019 (COVID-19) pandemic. However, there remains no vaccine that is clinically available to treat or prevent invasive fungal diseases, including cryptococcal meningoencephalitis. This fungal disease is uniformly fatal without treatment and has a global mortality rate of over 70%. Despite a dire need for an effective cryptococcal vaccine, there are many scientific and economic challenges to overcome prior to making it a reality. Here, we discuss some of these challenges as well as steps that the community is taking for commercialization of effective cryptococcal vaccines.

High‐entropy alloys (HEAs) have attracted widespread attention as both structural and functional materials owing to their huge multielement composition space and unique high‐entropy mixing structure. Recently, emerging HEAs, either in nano or highly porous bulk forms, are developed and utilized for various catalytic and clean energy applications with superior activity and remarkable durability. Being catalysts, HEAs possess some unique advantages, including (1) a multielement composition space for the discovery of new catalysts and fine‐tuning of surface adsorption (i.e., activity and selectivity), (2) diverse active sites derived from the random multielement mixing that are especially suitable for multistep catalysis, and (3) a high‐entropy stabilized structure that improves the structural durability in harsh catalytic environments. Benefited from these inherent advantages, HEA catalysts have demonstrated superior catalytic performances and are promising for complex carbon (C) and nitrogen (N) cycle reactions featuring multistep reaction pathways and many different intermediates. However, the design, synthesis, characterization, and understanding of HEA catalysts for C‐ and N‐involved reactions are extremely challenging because of both complex high‐entropy materials and complex reactions. In this review, we present the recent development of HEA catalysts, particularly on their innovative and extensive syntheses, advanced (in situ) characterizations, and applications in complex C and N looping reactions, aiming to provide a focused view on how to utilize intrinsically complex catalysts for these important and complex reactions. In the end, remaining challenges and future directions are proposed to guide the development and application of HEA catalysts for highly efficient energy storage and chemical conversion toward carbon neutrality. A review of the recent progress, challenges, and perspective of the syntheses, structures, and characterizations of high‐entropy alloy catalysts, and their applications in complex carbon and nitrogen looping reactions.

Cryptococcosis claims close to 200,000 lives annually. There is no vaccine clinically available for this fungal disease. Systemic cryptococcosis is fatal without treatment. Globally, this disease kills 180,000 of the 225,000 infected people each year, even with the use of antifungal therapies. Currently, there is no vaccine to prevent cryptococcosis. Previously, we discovered that Znf2, a morphogenesis regulator that directs Cryptococcus yeast-to-hyphal transition, profoundly affects cryptococcal interaction with the host—overexpression of ZNF2 drives filamentous growth, attenuates cryptococcal virulence, and elicits protective host immune responses. Importantly, immunization with cryptococcal cells overexpressing ZNF2 , either in live or heat-inactivated form, offers significant protection to the host from a subsequent challenge by the otherwise lethal wild-type H99 strain. We hypothesize that cellular components enriched in ZNF2 oe cells are immunoprotective. Here, we discovered that serum from protected animals vaccinated with inactivated ZNF2 oe cells recognizes cryptococcal antigens that reside within the capsule. Consistently, capsule is required for immunoprotection offered by ZNF2 oe cells. Interestingly, the serum from protective animals recognizes antigens in both wild-type yeast cells and ZNF2 oe cells, with higher abundance in the latter. Consequently, even the heat-inactivated wild-type cells become immunoprotective with an increased vaccination dose. We also found that disruption of a chromatin remodeling factor Brf1, which is important for initiation of filamentation by Znf2, reduces the antigen level in ZNF2 oe cells. Deletion of BRF1 drastically reduces the protective effect of ZNF2 oe cells in both live and heat-killed forms even though the ZNF2 oe brf1 Δ strain itself is avirulent. Collectively, our findings underscore the importance of identifying the subset of cryptococcal surface factors that are beneficial in host protection. IMPORTANCE Cryptococcosis claims close to 200,000 lives annually. There is no vaccine clinically available for this fungal disease. Many avirulent mutant strains do not provide protection against cryptococcosis. We previously discovered that hyphal ZNF2 oe strains elicit protective host immune responses both in the live and heat-inactivated forms. Here we seek to understand the mechanism underlying the host protection provided by ZNF2 oe cells. We discovered increased accumulation of antigens located within the caspusle of ZNF2 oe cells and consequently the requirement of the capsule for ZNF2 oe strain-elicited host protection. Furthermore, genetically blocking the ability of ZNF2 oe cells to grow in the hyphal form significantly reduces antigen accumulation and impairs the ability of ZNF2 oe strain to provide host protection. Our findings highlight the importance of identifying the Znf2-regulated capsular surface factors that are fundamental in host protection.

The combination of immunotherapy with platinum-based chemotherapy has become the first-line treatment for patients with advanced non–small cell lung cancer (NSCLC) with negative driver gene mutations. However, finding an ideal chemotherapeutic regimen for immunotherapy and exploring the underlying mechanism have noticeably attracted clinicians’ attention. In this study, we found that cisplatin induced ferroptosis of tumor cells, followed by N1 neutrophil polarization in the tumor microenvironment, which in turn remodeled the “cold” tumor to a “hot” one through enhancing T-cell infiltration and Th1 differentiation. Based on the important role of tumor ferroptosis in the immune-promoting effect of cisplatin, we noticed that the combination of a ferroptosis activator showed a synergistic effect with chemoimmunotherapy of epidermal growth factor receptor (EGFR)-mutant NSCLC, which would be an effective strategy to overcome immunotherapy resistance in NSCLC patients harboring driver mutations.