Biology subjects

Liu, Z.-P.

Publications and source records attributed to Liu, Z.-P..

3 recordsLinked to original sources

bioRxiv2021

Poly-glutamine-dependent self-association as a potential mechanism for regulation of androgen receptor activity

The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails dramatic epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC.

cancer biology↗

bioRxiv2020

Hepatic FGF21 mediates tissue tolerance during bacterial inflammation by preserving cardiac function

Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor-21 (FGF21), and decreases survival. Consistent with this observation, FGF21 deficient mice are more susceptible to mortality from endotoxemia and poly-bacterial peritonitis, but not viral infection. Here we report that increased circulating FGF21 during bacterial inflammation is hepatic-derived, promotes cardiac function, and is required for survival. FGF21 signaling downstream of its obligate co-receptor beta-Klotho (KLB) is required. However, mice with central nervous system or adipose-specific deletion of Klb do not demonstrate any difference in response to bacterial inflammation, suggesting that multiple tissues and/or a novel FGF21 target tissue are required for the full protective effect of FGF21. These data suggest that hepatic FGF21 is a novel cardioprotective factor in bacterial sepsis. eTOC SummaryIn response to bacterial inflammation, hepatic fibroblast growth factor 21 (FGF21), an endocrine hormone that mediates adaptive responses to metabolic stresses such as starvation, promotes survival by supporting heart function.

immunology↗

bioRxiv2020

A novel oxidase from Alcaligenes sp. HO-1 oxidizes hydroxylamine to N2

Hydroxylamine is a key intermediate of microbial ammonia oxidation and plays an important role in the biogeochemical cycling of N-compounds. Hydroxylamine is oxidized to NO or N2O by hydroxylamine oxidases or cytochrome P460 from heterotrophic or autotrophic bacteria, but its enzymatic oxidation to N2 has not yet been observed. Here, we report on the discovery of a novel oxidase that converts hydroxylamine to N2 from the newly isolated heterotrophic nitrifier Alcaligenes strain HO-1. Strain HO-1 accumulated hydroxylamine and produced N2 from ammonia oxidation. Using transcriptome analysis and heterologous expression via fosmid library screening, we identified three genes (dnfABC) of strain HO-1 that enabled E. coli cells not only to produce hydroxylamine from 15N-labelled ammonium but also to further convert it to 15N2. The three genes were individually cloned and expressed, and their translational products DnfA, DnfB, and DnfC were purified. In vitro DnfA bound to hydroxylamine and catalyzed the conversion of hydroxylamine to N2 in the presence of FAD, NADH and O2. Thus, DnfA was identified as a novel hydroxylamine oxidase and catalyzed a previously unknown N-N bond forming reaction with a yet-to-be discovered mechanism. DnfA homologs were detected in different bacterial groups, suggesting that hydroxylamine oxidation to nitrogen might occur in additional microbial taxa.

microbiology↗