Biology subjects

Hu, G.

Publications and source records attributed to Hu, G..

150 records · Page 9Linked to original sources

bioRxiv2018

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans

The battle for iron between invading microorganisms and mammalian hosts is a pivotal determinant of the outcome of infection. The pathogenic fungus, Cryptococcus neoformans, employs multiple mechanisms to compete for iron during cryptococcosis, a disease primarily of immunocompromised hosts. In this study, we examined the role of endocytic trafficking in iron uptake by characterizing a mutant defective in the Sec1/Munc18 (SM) protein Vps45. This protein is known to regulate the machinery for vesicle trafficking and fusion via interactions with SNARE proteins. As expected, a vps45 deletion mutant was impaired in endocytosis and showed sensitivity to trafficking inhibitors. The mutant also showed poor growth on iron-limited media and a defect in transporting the Cfo1 ferroxidase of the high-affinity iron uptake system from the plasma membrane to the vacuole. Remarkably, we made the novel observation that Vps45 also contributes to mitochondrial function in that a Vps45-Gfp fusion protein associated with mitotracker, and a vps45 mutant showed enhanced sensitivity to inhibitors of electron transport complexes as well as changes in mitochondrial membrane potential. Consistent with mitochondrial function, the vps45 mutant was impaired in calcium homeostasis. To assess the relevance of these defects for virulence, we examined cell surface properties of the vps45 mutant and found increased sensitivity to agents that challenge cell wall integrity and antifungal drugs. A change in cell wall properties was consistent with our observation of altered capsule polysaccharide attachment, and with attenuated virulence in a mouse model of cryptococcosis. Overall, our studies reveal a novel role for Vps45-mediated trafficking for iron uptake, mitochondrial function and virulence.

microbiology↗

bioRxiv2018

Role of clathrin-mediated endocytosis in the use of heme and hemoglobin by the fungal pathogen Cryptococcus neoformans

Heme is a major source of iron for pathogens of humans, and its use is critical in determining the outcome of infection and disease. Cryptococcus neoformans is an encapsulated fungal pathogen that causes life-threatening infections in immunocompromised individuals. C. neoformans effectively uses heme as an iron source but the underlying mechanisms are poorly defined. Non-iron metalloporphyrins (MPPs) are toxic analogues of heme and are thought to enter microbial cells via endogenous heme acquisition systems. We therefore carried out a mutant screen for susceptibility against manganese metalloporphyrin (Mn MPP) to identify new components for heme uptake in C. neoformans. We identified several genes involved in signaling, DNA repair, sugar metabolism and trafficking that play important roles in susceptibility to Mn MPP and in the use of heme as an iron source. We focused on investigating the role of clathrin-mediated endocytosis (CME) and found that several components of CME including Chc1, Las17, Rvs161 and Rvs167 are required for growth on heme and hemoglobin, and for endocytosis and intracellular trafficking of these molecules. We show that the hemoglobin uptake process in C. neoformans involves clathrin heavy chain, Chc1, which appears to co-localize with hemoglobin containing-vesicles and to potentially assist in proper delivery of hemoglobin to the vacuole. Additionally, C. neoformans strains lacking Chc1, Las17, Rvs161, or Rvs167 were defective in the elaboration of several key virulence factors and a las17 mutant was avirulent in a mouse model of cryptococcosis. Overall, this study unveils crucial functions of CME in the use of heme iron by C. neoformans and reveals a role for CME in fungal pathogenesis.

microbiology↗

bioRxiv2018

PIP5k1 β controls bone homeostasis through modulating both osteoclast and osteoblast differentiation

PIP5K1{beta} is crucial to generation of phosphotidylinosotol (4, 5) P2. PIP5K1{beta} participates in numerous cellular activities, such as B cell and platelet activation, cell phagocytosis and endocytosis, cell apoptosis, and cytoskeletal organization. In the present work, we aimed to make insight into the function of PIP5K1{beta} in osteoclastogenesis and osteogenesis to provide promising strategies for osteoporosis prevention and treatment. We discovered that PIP5k1{beta} deletion in mice resulted in obvious bone loss and PIP5K1{beta} was highly expressed both during osteoclast and osteoblast differentiation, besides, PIP5K1{beta} deletion enhanced the proliferation and migration of BMMs to promote osteoclast differentiation. PIP5k1{beta}-/- osteoclast exhibited normal cytoskeleton architecture but stronger resorption activity. PIP5k1{beta} deficiency also promoted activation of MAPK and Akt signaling, enhanced TRAF6 and c-Fos expression, facilitated the expression and nuclear translocation of NFATC1 and upregulated Grb2 expression, thereby accelerating osteoclast differentiation and function. Finally, PIP5K1{beta} enhanced osteoblast differentiation by upregulating master genes expression through triggering smad1/5/8 signaling. Thereby, PIP5K1{beta} modulate bone homeostasis and remodeling.

cell biology↗

bioRxiv2017

An analytical framework to understand regulatory novelty accompanying allopolyploidization

Allopolyploidy is a prevalent process in plants, having important physiological, ecological, and evolutionary consequences. Massive, genome-wide transcriptomic rewiring in response to genomic merger and doubling has been demonstrated in many allopolyploid systems, encompassing a diversity of phenomena, including homoeolog expression bias, genome dominance, expression-level dominance, and revamping of co-expression networks. Here we present an analytical framework to reconcile these patterns of regulatory novelty as governed by distinct sets of intra- and inter-subgenome cis-trans relationships. This approach is a novel extension of classic allele-specific expression analysis to incorporate and distinguish the separate effects of parental regulatory interactions as well as further complications at the allopolyploid level. We demonstrated that the cis-trans framework devised not only offers new perspective on disentangling genetic from epigenetic and higher-order effects that impact gene expression, but also provides the conceptual basis and tools to unify recently presented models for both genome-wide expression dominance and biased fractionation in allopolyploids.

evolutionary biology↗

bioRxiv2017

Extracting active modules from multilayer PPI network: a continuous optimization approach

Active modules identification has received much attention due to its ability to reveal regulatory and signaling mechanisms of a given cellular response. Most existing algorithms identify active modules by extracting connected nodes with high activity scores from a graph. These algorithms do not consider other topological properties such as community structure, which may correspond to functional units. In this paper, we propose an active module identification algorithm based on a novel objective function, which considers both and network topology and nodes activity. This objective is formulated as a constrained quadratic programming problem, which is convex and can be solved by iterative methods. Furthermore, the framework is extended to the multilayer dynamic PPI networks. Empirical results on the single layer and multilayer PPI networks show the effectiveness of proposed algorithms.\n\nAvailability: The package and code for reproducing all results and figures are available at https://github.com/fairmiracle/ModuleExtraction.

bioinformatics↗

bioRxiv2017

A mouse model of necrotic biliary pancreatitis induced by combining gallstone formation and ligation of the biliary-pancreatic duct

ObjectiveThe aim of the present investigation is to develop a mouse model of biliary pancreatitis with characteristics of both gallstone formation and pancreatitis, mimicking the human etiology and pathphysiological character.\n\nDesignMale C57BL/6 mice were fed with chow, high fat/cholesterol and lithogenic diet for 12 weeks respectively. Laparotomy was done followed by ligation of pancreatic duct (PD), bile duct and pancreatic duct (BPD), or sham operation.\n\nResultsLittle or no evidence of pancreatitis was observed in PD group of mice fed with chow or high fat/cholesterol diet, or in the tail of pancreata removed from animals fed with lithogenic diet. In the head of pancreas, pancreas damage was dramatically more severe in the lithogenic group. When bile reflux was blocked by BPD, pancreas damage markedly reduced to level of chow diet group. The lithogenic diet group also developed significantly more severe multi organ dysfunction syndrome (MODS) in the lung, kidney and liver. The severity of pancreatitis is associated with persistent high bile level of cholesterol and bile acid after obstruction of the biliary-pancreatic duct. Cholesterol crystal aggravated injury of pancreatic acinar cells caused by taurocholate. After obstruction of the biliary-pancreatic duct, in the lithogenic diet group, liver Abcg8 and Cyp7a1 was up-regulated, compared to the control group.\n\nConclusionWe developed a mouse model of severe biliary pancreatitis in both local pancreas damage and MODS. This model provides a sound explanation for the Opie theory dilemma and a potential therapeutical direction in clinical practice as well.\n\nSummary statementA biliary pancreatitis has characters of both gallstone and pancreatitis, mimicking human etiology and pathophysiology, which gave a clear answer to the long time Opie theory dilemma.

pathology↗