Biology subjects

Mo, X.

Publications and source records attributed to Mo, X..

27 records · Page 2Linked to original sources

bioRxiv2021

Interferon-gamma Induces Melanogenesis Via Post-Translational Modification of Tyrosinase

Melanogenesis (melanin pigment production) in melanocytes is canonically stimulated by the alpha-melanocyte stimulating hormone (MSH), which activates the cyclic-AMP-mediated expression of the melanocyte inducing transcription factor (MITF) and its downstream melanogenic genes, including the principal rate-limiting melanogenic enzyme tyrosinase (Tyr). Here we report that interferon-gamma (IFNG; type II interferon), but not IFN-alpha (a type I interferon), induces a noncanonical melanogenic pathway. Inhibition of IFNG pathway by the JAK inhibitor ruxolitinib or knocking out Stat1 abrogated the IFNG-induced melanogenesis. Interestingly, IFNG-induced melanogenesis was independent of MITF. IFNG markedly increased the Tyr protein expression but did not affect the mRNA expression, suggesting a post-translational regulatory mechanism. In contrast, IFNG had no effect on the expression of other melanogenesis-related proteins, e.g. tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct). Glycosidase digestion assays revealed that IFNG treatment increased the mature glycosylated form of Tyr, but not its de novo synthesis. Moreover, cycloheximide chase assay showed that degradation of Tyr was decreased in IFNG-treated cells. These results suggest that the IFNG-STAT1 pathway regulates melanogenesis via modulation of the post-translational processing and protein stability of Tyr. SIGNIFICANCEThe canonical pathway that controls melanogenesis in melanocytes is activated by the alpha melanocyte stimulating hormone (MSH) via its receptor MC1R, which activates the cyclic-AMP-mediated expression of the melanocyte master regulator MITF and its downstream target genes involved in the melanogenic process. Here we report a novel non-canonical melanogenic pathway that is mediated via the Interferon-gamma cytokine signaling. We show that this non-canonical pathway is independent of MITF-mediated gene expression, but rather functions via post-translational modification of the principal melanogenic enzyme Tyrosinase.

molecular biology↗

bioRxiv2021

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer

Comprehensive sequencing of patient tumors reveals numerous genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative High Throughput differential Screening (qHT-dS) platform. Coupling of highly sensitive BRET biosensors with miniaturized co-expression in an ultra-HTS format allows large-scale monitoring of interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. Screening of 13,392 interactions with 1,474,560 data points revealed a landscape of gain-of-interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E-KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

cancer biology↗

bioRxiv2021

Pharmacological rescue of tumor intrinsic STING expression and immune response in LKB1-mutant lung cancer via the IAP-JAK regulatory axis

Harnessing the power of the immune system to treat cancer has become a core clinical approach. However, rewiring of intrinsic circuitry enables tumor cells to escape immune attacks, leading to therapeutic failure. Pharmacological strategies to reverse tumor genotype-dictated therapeutic resistance are urgently needed to advance precision immunotherapy. Here, we identify antagonists of Inhibitor of Apoptosis Protein (IAP) as potent sensitizers that restore immune-dependent killing of LKB1-mutant lung cancer cells. Mechanistic studies reveal an LKB1-IAP-JAK trimolecular complex that bridges the LKB1-mutant genotype with IAP-dependency and a STING-deficiency-mediated immune resistance phenotype. Ultimately, inhibition of IAP re-establishes JAK-regulated STING expression and DNA sensing pathway as well as enhanced cytotoxic immune cell infiltration and selective immune-dependent anti-tumor activity in an LKB1-mutant immune-competent mouse model. Thus, IAP-JAK-modulatory strategies, like IAP inhibitors, offer promising immunotherapy adjuvants to re-establish the responsiveness of "immunologically-cold" LKB1-mutant tumors to immune checkpoint inhibitors or STING-directed therapies.

cancer biology↗

bioRxiv2021

brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

Cancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.

cancer biology↗

bioRxiv2021

Survival mechanism of a novel marine multistress-tolerant Meyerozyma guilliermondii GXDK6 under high NaCl stress as revealed by integrative omics analysis

A novel strain named Meyerozyma guilliermondii GXDK6 was provided in this work, which was confirmed to survive independently under high salt stress (12% NaCl) or co-stress condition of strong acid (pH 3.0) and high salts (10% NaCl) without sterilization. Its survival mechanism under high salt stress was revealed by integrated omics for the first time. Whole-genome analysis showed that 14 genes (e.g., GPD1 and FPS1) of GXDK6 relevant to salt tolerance were annotated and known to belong to various salt-resistant mechanisms (e.g., regulation of cell signal transduction and glycerol metabolism controls). Transcriptome sequencing results indicated that 1220 genes (accounting for 10.15%) of GXDK6 were differentially transcribed (p < 0.05) when GXDK6 growth was under 10% stress for 16 h, including important novel salt-tolerant-related genes (e.g., RTM1 and YHB1). Proteomics analysis demonstrated that 1005 proteins (accounting for 27.26%) of GXDK6 were differentially expressed (p < 0.05) when GXDK6 was stressed by 10% NaCl. Some of the differentially expressed proteins were defined as the novel salt-tolerant related proteins (e.g., sugar transporter STL1 and NADPH-dependent methylglyoxal reductase). Metabolomic analysis results showed that 63 types of metabolites (e.g., D-mannose, glycerol and inositol phosphate) of GXDK6 were up- or downregulated when stressed by 10% NaCl. Among them, D-mannose is one of the important metabolites that could enhance the salt-tolerance survival of GXDK6. IMPORTANCEMicrobial contamination is a huge obstacle in industrial fermentation. The emergence of multistress-tolerant microorganism is expected to realize industrial fermentation without sterilization by controlling specific conditions. However, microorganisms eligible for non-sterile fermentation are required to survive independently under the selected special conditions for the fermentation conditions to be controlled to avoid microbial contamination. Here, a novel marine Meyerozyma guilliermondii was presented, which is able to survive well under high salt stress, its survival mechanism was systematically revealed by integrated omics technology. In addition, finding that NaCl stress could also stimulate the biosynthesis of functional metabolites from GXDK6 (e.g., calcitriol and didemnin B). Among the functional metabolites, calcitriol biosynthesis via microbial method was rarely reported. Thus, its biosynthetic mechanism was further revealed. The findings in this study contributed to understanding the survival mechanism of M. guilliermondii under high salt stress, and the development of new molecular drugs from M. guilliermondii GXDK6. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/450280v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@928135org.highwire.dtl.DTLVardef@60c713org.highwire.dtl.DTLVardef@1adb19dorg.highwire.dtl.DTLVardef@67caaa_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2021

Unravelling processes between phenotypic plasticity and population dynamics in migratory birds

O_LIPopulations can rapidly respond to environmental change via adaptive phenotypic plasticity, which can also modify interactions between individuals and their environment, affecting population dynamics. Bird migration is a highly plastic resource-tracking strategy in seasonal environments. However, the link between the population dynamics of migratory birds and migration strategy plasticity is not well understood. C_LIO_LIThe quality of staging habitats affects individuals migration timing and energy budgets in the course of migration, and can consequently affect individuals breeding and overwintering performance, and impact population dynamics. Given staging habitats being lost in many parts of the world, our goal is to investigate responses of individual migration strategies and population dynamics in the face of loss of staging habitat, and to identify the key processes connecting them. C_LIO_LIWe started by constructed and analysed a general full-annual-cycle individual-based model with a stylized migratory population to generate hypotheses on how changes in the size of staging habitat might drive changes in individual stopover duration and population dynamics, and to identify the key processes connecting them. Next, through the interrogation of census data, we tested these hypotheses by analysing population trends and stopover duration of migratory waterbirds experiencing loss of staging habitat. C_LIO_LIWe found empirical support for our modelling-identified hypotheses: the loss of staging habitat generates plasticity in migration strategies, with individuals remaining on the staging habitat for longer to obtain food due to a reduction in per capita food availability. The subsequent increasing population density on the staging habitat has knock on effects on population dynamics in the breeding and overwintering stage. C_LIO_LIOur results demonstrate how environmental change that impacts one energetically costly life history stage in migratory birds can have population dynamics impacts across the entire annual cycle via phenotypic plasticity. C_LI

ecology↗

bioRxiv2020

Structural insights into the recognition of histone H3Q5 serotonylation by WDR5

Serotonylation of histone H3Q5 (H3Q5ser) is a recently identified posttranslational modification of histones that apparently acts as a permissive marker for gene activation in synergy with H3K4me3 during neuronal cell differentiation. However, any proteins which specifically recognize H3Q5ser remain unknown. Here, we discovered that WDR5 interacts with the N-terminal tail of histone H3 and functions as a reader for H3Q5ser. Crystal structures of WDR5 in complex with H3Q5ser and H3K4me3Q5ser peptides revealed that the serotonyl group is accommodated in a shallow surface pocket of WDR5. Experiments in neuroblastoma cells demonstrate that WDR5 colocalizes with H3Q5ser in the promoter regions of cancer-promoting genes, where it promotes gene transcription to induce cell proliferation. Thus, beyond revealing a previously unknown mechanism through which WDR5 reads H3Q5ser to activate transcription, our study suggests that this WDR5-H3Q5ser mediated epigenetic regulation apparently promotes tumorigenesis.

biochemistry↗

bioRxiv2019

Synthetic lethality targeting LKB1 mutant and EGFR wild type human non-small cell lung cancer cells by glucose starvation and SGLT2 inhibition

In this study, we aimed to discover novel therapeutic approaches targeting non-small cell lung cancer (NSCLC) patients without EGFR mutation. First, we found that mutations of EGFR and LKB1 are mutually exclusive in NSCLC. EGFR-WT/LKB1-mutant cells are resistant to EGFR inhibitor erlotinib but are highly susceptible to glucose starvation or SGLT2 inhibitor canagliflozin. Mechanistically, in these cells, glucose starvation causes suppression of AMPK and induction of oxidative stress, leading to cell death. Finally, canagliflozin effectively reduces tumor growth of EGFR-WT/LKB1-mutant NSCLC cells in the mice xenograft model. Our data thus demonstrate that synthetic lethality can be achieved by glucose starvation or SGLT2 inhibition in EGFR-WT/LKB1-mutant NSCLC.\n\nSIGNIFICANCEAt present, EGFR inhibitor-based targeted therapy can only benefit those non-small cell lung cancer (NSCLC) patients with EGFR mutation. Therefore, there is an urgent need to develop alternate targeted therapy for NSCLC with WT EGFR. In this study, we found that mutations of EGFR and LKB1 are mutually exclusive in NSCLC, and more importantly, synthetic lethality can be achieved in EGFR-WT/LKB1-mutant NSCLC cells with glucose starvation or SGLT2 inhibition. Since SGLT2 inhibitors such as canagliflozin are FDA-approved drugs for type II diabetes, our study thus points out a possibility of developing SGLT2 inhibitors as a targeted therapy for NSCLC patients with WT EGFR and mutant LKB1, which will benefit about 15-30% of NSCLC patients.\n\nHIGHLIGHTSO_LIEGFR and LKB1 mutations are mutually exclusive in NSCLC\nC_LIO_LIEGFR-WT/LKB1-mutant NSCLC cells are sensitive to cell death induced by glucose starvation and SGLT2 inhibition\nC_LIO_LIGlucose starvation suppresses AMPK activity in LKB1-mutant NSCLC cells\nC_LIO_LISGLT2 inhibitor canagliflozin causes synthetic lethality in LKB1-mutant NSCLC cells\nC_LI

cancer biology↗

bioRxiv2018

Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population

The strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the real or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQ1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 x 10-36, OR=2.29). Further stepwise conditional analysis revealed that DR{beta}1:37N has an independent protective effect on ACPA-positive RA (P = 5.81 x 10-16, OR=0.49). The DQ1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 x 10-5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQ1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DR{beta}1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.\n\nIn this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

genetics↗