Biology subjects

Zheng, Q.

Publications and source records attributed to Zheng, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Preventing escape and malfunction of recoded cells due to tRNA base changes

Engineering the genetic code restricts DNA transfer (cellular bioisolation) and enables new chemistries via non-standard amino acid incorporation. These distinct properties make recoded cells state-of-the-art safe technologies. However, evolutionary pressures may endanger the longevity of the recoding. Here, we reveal that recoded Escherichia coli lacking 18,214 serine codons and two tRNASer can express wild-type antibiotic resistance genes and escape up to seven orders of magnitude faster than expected. We show a two-step escape process whereby recoded cells mistranslate antibiotic resistance genes to survive until modified or mutated tRNAs reintroduce serine into unassigned codons. We developed genetic-code-sensitive kill switches that sense serine incorporation and prevent cellular escape while preserving encoding of three distinct non-standard amino acids. This work lays the foundation for the long-term controlled function of cells that incorporate new chemistries, with implications for the design, use, and biosafety of synthetic genomes in clinical and environmental applications where physical containment is insufficient.

synthetic biology↗

bioRxiv2024

Temporal-spatially metabolic reprogramming rewires the H3K27ac landscape to enable the initiation of liver regeneration

The liver possesses extensive regenerative capacity. Nevertheless, the most proximal events driving the transition from quiescent to proliferative hepatocytes remain largely elusive. Using the combination of spatiotemporal metabolomics and transcriptomics, our study mapped out the temporal-spatial landscape of metabolic reprogramming, epigenetic remodeling, and transcriptomic rewiring from 3 to 12 hours post-partial hepatectomy. Specifically, we identified a profound metabolic shift towards hyperactive fatty acid oxidation (FAO) and suppressed phospholipid biosynthesis during the preparation phase of liver regeneration, which were surprisingly reversed afterwards. FAO-dependent accumulation of Acetyl-CoA particularly remodeled H3K27ac landscape. These metabolic reprograming and epigenetic regulation were spatially specific, aligning with the zonation of hepatocyte proliferation. Blocking FAO in etomoxir-treated or hepatocyte-specific Cpt1a knockout mice, suppressing Acetyl-CoA biosynthesis, and inhibiting histone acetyltransferase all resulted in lethal liver regeneration deficiency. CUT&Tag analysis further revealed that the reshaping of H3K27ac profiles favored the transcription of genes associated with cell cycle transition and mitosis, and rewired the metabolic gene network. Collectively, we highlight a previously underappreciated role of FAO in epigenetic remodeling that is essential for the initiation of liver regeneration, offering exciting opportunity for the rescue of regeneration-deficient livers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC="FIGDIR/small/602368v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@8dd836org.highwire.dtl.DTLVardef@6ddb27org.highwire.dtl.DTLVardef@4f1e49org.highwire.dtl.DTLVardef@4d7afe_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Alpine lakes harbor diverse, endemic and structurally unique RNA viruses

Alpine lakes, characterized by isolation, low temperatures, oligotrophic conditions, and intense ultraviolet radiation, remain a poorly explored ecosystem for RNA viruses. Here, we present the first comprehensive metatranscriptomic study of RNA viruses in Lake Nam Co, a high-altitude alkaline saline lake on the Tibetan Plateau. Using a combination of sequence- and structure-based homology searches, we identified 742 RNA virus species, including 383 novel genus-level groups and 84 novel family-level groups exclusively found in Lake Nam Co. These findings significantly expand the known diversity of the Orthornavirae, uncovering evolutionary adaptations such as permutated RNA-dependent RNA polymerase (RdRP) motifs and distinct RNA secondary structures. Notably, 14 previously unknown RNA virus families potentially infecting prokaryotes were predicted, broadening the known host range of RNA viruses and questioning the traditional assumption that RNA viruses predominantly target eukaryotes. The presence of auxiliary metabolic genes (AMGs) in viral genomes suggested that RNA viruses (families f.0102 and Nam-Co_family_51) exploit host energy production mechanisms in energy-limited alpine lakes. Low nucleotide diversity, SNP frequencies, and pN/pS ratios indicate strong purifying selection in Nam Co viral populations. Our findings offer insights into RNA virus evolution and ecology, highlighting the importance of extreme environments in uncovering hidden viral diversity, and further shed light into their potential ecological implications, particularly in the context of climate change. Significance StatementThis study unveils the hidden diversity and complexity of RNA viruses in the high-altitude ecosystem of Lake Nam Co, significantly expanding the known RNA virome. The discovery of novel viral clades, expanded potential host ranges, and unique evolutionary adaptations emphasizes the importance of exploring extreme environments to uncover viral diversity and evolutionary pathways. Our findings offer critical insights into viral evolution, host-virus interactions, and the ecological roles of RNA viruses, particularly in the context of climate change and environmental resilience.

microbiology↗

bioRxiv2024

Synthetic genomes unveil the effects of synonymous recoding

Engineering the genetic code of an organism provides the basis for (i) making any organism safely resistant to natural viruses and (ii) preventing genetic information flow into and out of genetically modified organisms while (iii) allowing the biosynthesis of genetically encoded unnatural polymers1-4. Achieving these three goals requires the reassignment of multiple of the 64 codons nature uses to encode proteins. However, synonymous codon replacement--recoding--is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using whole-genome synthesis, multiplexed directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple recoded genomes. Using this information, we assemble a synthetic Escherichia coli genome in seven sections using only 57 codons to encode proteins. By discovering the rules responsible for the lethality of synonymous recoding and developing a data-driven multi-omics-based genome construction workflow that troubleshoots synthetic genomes, we overcome the lethal effects of 62,007 synonymous codon swaps and 11,108 additional genomic edits. We show that synonymous recoding induces transcriptional noise including new antisense RNAs, leading to drastic transcriptome and proteome perturbation. As the elimination of select codons from an organisms genetic code results in the widespread appearance of cryptic promoters, we show that synonymous codon choice may naturally evolve to minimize transcriptional noise. Our work provides the first genome-scale description of how synonymous codon changes influence organismal fitness and paves the way for the construction of functional genomes that provide genetic firewalls from natural ecosystems and safely produce biopolymers, drugs, and enzymes with an expanded chemistry.

synthetic biology↗

bioRxiv2024

pH-Controlled chemoselective rapid azo-coupling reaction (CRACR) enables global profiling of serotonylation proteome in cancer cells

Serotonylation has been identified as a novel protein post-translational modification for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known as TGM2 or TGase2) was proven to act as the main "writer" enzyme for this PTM and a number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, serotonin transporter, and histone H3) have been characterized as the substrates of serotonylation. However, due to the lack of pan-specific antibodies for serotonylated glutamine, the precise enrichment and proteomic profiling of serotonylation still remain challenging. In our previous research, we developed an aryldiazonium probe to specifically label protein serotonylation in a bioorthogonal manner, which depended on a pH-controlled chemoselective rapid azo-coupling reaction (CRACR). Here, we report the application of a photoactive aryldiazonium-biotin probe for the global profiling of serotonylation proteome in cancer cells. Thus, over 1,000 serotonylated proteins were identified from HCT 116 cells, many of which are highly related to carcinogenesis. Moreover, a number of modification sites of these serotonylated proteins were determined, attributed to the successful application of our chemical proteomic approach. Overall, these findings provided new insights into the significant association between cellular protein serotonylation and cancer development, further suggesting that to target TGM2-mediated monoaminylation may serve as a promising strategy for cancer therapeutics. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/593574v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@67e538org.highwire.dtl.DTLVardef@f9f722org.highwire.dtl.DTLVardef@cfe5fdorg.highwire.dtl.DTLVardef@104674f_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 (i.e., glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/591460v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a3e9dorg.highwire.dtl.DTLVardef@104ecddorg.highwire.dtl.DTLVardef@5ab948org.highwire.dtl.DTLVardef@3a5d8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

ScRNA-seq and scATAC-seq reveal that sertoli cell mediate spermatogenesis disorders through stage-specific communications in non-obstructive azoospermia

Non-obstructive azoospermia (NOA) belongs to male infertility due to spermatogenesis failure. However, evidence for cell type-specific abnormalities of spermatogenesis disorders in NOA remains lacking. We performed single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on testicular tissues from patients with obstructive azoospermia(OA) and NOA. HE staining confirmed the structural abnormalities of the seminiferous tubules in NOA patients. We identified 12 germ cell subtypes (spermatogonial stem cell-0 (SSC0), SSC1, SSC2, diffing-spermatogonia (Diffing-SPG), diffed-spermatogonia (Diffed-SPG), pre-leptotene (Pre-Lep), leptotene-zygotene (L-Z), pachytene (Pa), diplotene (Di), spermatids-1 (SPT1), SPT2, and SPT3) and 8 Sertoli cell subtypes (SC1-SC8). Among them, three novel Sertoli cell subtypes phenotypes were identified, namely SC4/immature, SC7/mature, and SC8/further mature Sertoli cells. For each germ or Sertoli cell subtype, we identified unique new markers, among which immunofluorescence confirmed co-localization of ST3GAL4, A2M, ASB9, and TEX19 and DDX4 (classical marker of germ cell). PRAP1, BST2, and CCDC62 were co-expressed with SOX9 (classical marker of Sertoli cell) in testes tissues also confirmed by immunofluorescence. The interaction between germ cell subtypes and Sertoli cell subtypes exhibits stage-specific-matching pattern, as evidenced by SC1/2/5/7 involving in SSC0-2 development, SC3 participating in the whole process of spermiogenesis, SC4/6 participating in Diffing and Diffed-SPG development, and SC8 involving in the final stage of SPT3. This pattern of specific interactions between subtypes of germ cell and Sertoli cell was confirmed by immunofluorescence of novel markers in testes tissues. The interaction was mainly contributed by Notch1/2/3 signaling. Our study profiled the single-cell transcriptome of human spermatogenesis and provided many potentials molecular markers for developing testicular puncture specific marker kits for NOA patients. Impact statementThe specific interactions between Sertoli cell subtypes and different stages of germ subgroups maintain normal development of germ cells. SC3 subtype absence may be the key factor leading to NOA.

cell biology↗

bioRxiv2024

Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin

Histone monoaminylation (i.e., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/586010v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1bee3f7org.highwire.dtl.DTLVardef@1687013org.highwire.dtl.DTLVardef@1960bd0org.highwire.dtl.DTLVardef@1e19a04_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Map based cloning of CT2 and the pilot functional exploration in abiotic stress

Heterotrimeric G-proteins are multifunctional modulators that participate in a wide range of growth and developmental processes in eukaryotic species, from yeast to plants and animals. Component detection and the study of G protein signaling in most plants, including maize, are in the initial stages. In this study, we characterized a maize mutant, ct2, that showed a compact architecture and reproductive organ-related phenotypic variation. The target gene CT2 was cloned using bulked segregant analysis and map-based cloning. Gene structure prediction and phylogenetic analysis indicated that CT2 is a canonical G protein belonging to the monocotyledonous group. Promoter analysis of CT2 and RNA sequencing revealed cis-acting regulatory elements and differentially expressed genes involved in JA signaling and stress tolerance. The transcription of CT2 was repressed by NaCl and PEG treatments, and ct2 mutation in the ct2 line compromised stress tolerance in maize. On the basis of our results, we proposed a schema diagram of CT2-regulated biological process and their feedback on CT2 transcription. This research provides clues for further studies of CT2 function in hormone signaling and stress tolerance, which is beneficial for maize breeding through the screening and application of beneficial alleles.

molecular biology↗

bioRxiv2024

A series of spontaneously blinking dyes for super-resolution microscopy

Spontaneously blinking fluorophores permit the detection and localization of individual molecules without reducing buffers or caging groups, thus simplifying single-molecule localization microscopy (SMLM). The intrinsic blinking properties of such dyes are dictated by molecular structure and modulated by environment, which can limit utility. We report a series of tuned spontaneously blinking dyes with duty cycles that span two orders of magnitude, allowing facile SMLM in cells and dense biomolecular structures.

cell biology↗

bioRxiv2024

Assessing NGS-based computational methods for predicting transcriptional regulators with query gene sets

This article provides an in-depth review of computational methods for predicting transcriptional regulators with query gene sets. Identification of transcriptional regulators is of utmost importance in many biological applications, including but not limited to elucidating biological development mechanisms, identifying key disease genes, and predicting therapeutic targets. Various computational methods based on next-generation sequencing (NGS) data have been developed in the past decade, yet no systematic evaluation of NGS-based methods has been offered. We classified these methods into two categories based on shared characteristics, namely library-based and region-based methods. We further conducted benchmark studies to evaluate the accuracy, sensitivity, coverage, and usability of NGS-based methods with molecular experimental datasets. Results show that BART, ChIP-Atlas, and Lisa have relatively better performance. Besides, we point out the limitations of NGS-based methods and explore potential directions for further improvement. Key pointsO_LIAn introduction to available computational methods for predicting functional TRs from a query gene set. C_LIO_LIA detailed walk-through along with practical concerns and limitations. C_LIO_LIA systematic benchmark of NGS-based methods in terms of accuracy, sensitivity, coverage, and usability, using 570 TR perturbation-derived gene sets. C_LIO_LINGS-based methods outperform motif-based methods. Among NGS methods, those utilizing larger databases and adopting region-centric approaches demonstrate favorable performance. BART, ChIP-Atlas, and Lisa are recommended as these methods have overall better performance in evaluated scenarios. C_LI

bioinformatics↗

bioRxiv2024

Capturing Snapshots of Nucleosomal H2A K13/K15 Ubiquitination Mediated by the Monomeric E3 Ligase RNF168

AbstractsThe DNA damage repair regulatory protein RNF168, a monomeric RING-type E3 ligase, plays a crucial role in regulating cell fate and DNA repair by specific and efficient ubiquitination of the adjacent Lys13 and Lys15 sites at the H2A N-terminal tail. However, understanding how RNF168 coordinates with its cognate E2 enzyme UbcH5c to ubiquitinate H2AK13/15 site-specifically has long been hampered by the lack of high-resolution structures of RNF168 and UbcH5c[~]Ub in complex with nucleosomes. Here, we developed mechanism-based chemical trapping strategies and determined the cryo-EM structures of the RNF168/UbcH5c-Ub/NCP complex captured in transient H2AK13/15 monoubiquitination and adjacent dual-monoubiquitination reactions. Our structural analysis revealed that RNF168 stably binds to the nucleosomal H2A-H2B acidic patch through a basic helix with multiple interactions, which positions the UbcH5c active centre directly over the H2A N-terminus, providing a "helix-anchoring" mode for monomeric E3 ligase RNF168 on nucleosome in contrast to the "compass-binding" mode of dimeric E3 ligases. Furthermore, our chemically synthesized ubiquitinated histones have enabled the elucidation of the efficiency of Ub installation and the interplay between the initial and subsequent Ub modifications on the adjacent H2A K13 and K15 sites. Overall, our work not only provides structural snapshots of H2A K13/K15 site-specific monoubiquitination and adjacent dual-monoubiquitination, but also offers a near-atomic resolution structural framework for understanding how pathogenic mutations or physiological modifications affect the molecular function of RNF168 in H2A K13/15 ubiquitination.

biochemistry↗

bioRxiv2024

An opponent striatal circuit for distributional reinforcement learning

Machine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards -- an approach known as distributional reinforcement learning (RL)1. The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum2,3, but little is known about whether, where, and how neurons in this circuit encode information about higher-order moments of reward distributions4. To fill this gap, we used high-density probes (Neuropixels) to acutely record striatal activity from well-trained, water-restricted mice performing a classical conditioning task in which reward mean, reward variance, and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Remarkably, chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons -- D1 and D2 MSNs -- contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 MSNs5-15 to reap the computational benefits of distributional RL.

neuroscience↗

bioRxiv2023

An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinsons disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a promising vector for human CNS gene therapy.

neuroscience↗

bioRxiv2023

Spatiotemporal Profiling Unveiling the Cellular Organization Patterns and Local Protumoral Immune Microenvironment Remodeling in Early Lung Adenocarcinoma Progression

Spatial cellular organization patterns (COPs) in tumor microenvironment influence the tumor progression and therapeutic response, however, little is known about the cellular composition and functional potential of these multicellular structures during lung adenocarcinoma progression. Here, we integrate spatial transcriptomics with single cell RNA sequencing to characterize the local tumor and immunological landscape of samples from 8 patients with early-stage lung adenocarcinoma at different pathological stages. We identified ten COPs that show distinct associations with local immune states and clinical outcomes, including survival and therapy response. The local infiltration levels of regulatory and dysfunctional immune cells are increased with pathological progression. Cell-to-cell interactions between malignant cells and tumor microenvironment (TME) cells were involved in protumor immune state remodeling. Finally, we detected a group of malignant cells that were specifically located at the tumor boundary, representing a more aggressive state, were involved in the invasion of invasive adenocarcinoma (IAC). Altogether, these results can improve our understanding of the local microenvironment characteristics that underlie LUAD progression and may facilitate the identification of drug targets to prevent invasive progression and biomarkers for diagnosis.

cell biology↗

bioRxiv2023

Pervasive biases in proxy GWAS based on parental history of Alzheimer's disease

Almost every recent Alzheimers disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and non-random participation of parental illness survey, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that current AD GWAX provide highly misleading genetic correlations between AD risk and higher education which subsequently affects a variety of genetic epidemiologic applications involving AD and cognition. Our study sheds important light on the design and analysis of mid-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

genetics↗

bioRxiv2023

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer

The tissue microenvironment in prostate cancer is profoundly altered. While such alterations have been implicated in driving prostate cancer initiation and progression to aggressive disease, how prostate cancer cells and their precursors mediate those changes is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we performed extensive single-cell RNA-sequencing (scRNA-seq) and rigorous molecular pathology of the comparative biology between human prostate cancer and key time points in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues, with validation in a large external data set, revealed that cancer cell-intrinsic activation of MYC signaling was the top up-regulated pathway in human cancers, representing a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Likewise, numerous non-malignant cell states in the tumor microenvironment (TME), including non-cancerous epithelial, immune, and fibroblast cell compartments, were conserved across individuals, raising the possibility that these cell types may be a sequelae of the convergent MYC activation in the cancer cells. To test this hypothesis, we employed a GEMM of prostate epithelial cell-specific MYC activation in two mouse strains. Cell communication network and pathway analyses suggested that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogrammed the TME during carcinogenesis, leading to the emergence of cascading cell state alterations in neighboring epithelial, immune, and fibroblast cell types that paralleled key findings in human prostate cancer. Importantly, among these changes, the progression from a precursor-enriched to invasive-cancer-enriched state was accompanied by a cell-intrinsic switch from pro-immunogenic to immunosuppressive transcriptional programs with coinciding enrichment of immunosuppressive myeloid and Treg cells in the immune microenvironment. These findings implicate activation of MYC signaling in reshaping convergent aspects of the TME of prostate cancer as a common denominator across the otherwise well-documented molecular heterogeneity of human prostate cancer.

cancer biology↗

bioRxiv2023

Structure basis of the phytoplasma effector SAP05 recognition specificities to plant Rpn10 in ubiquitin-independent protein degradation

Recent research reported an effector protein SAP05 secreted by phytoplasma could hijack hostage Rpn10 subunit of proteasome and target degradation of GATA or SPL transcription factors (TFs) without ubiquitin. As a result, plant phenotypes will be reprogrammed to a state suitable for phytoplasma amplification and insect vector propagation which present prolonged growth cycles, witches broom-like proliferations of leaves and sterile shoots. We are curious about how could SAP05 target degradation bypassing the ubiquitin pathway and if there is any conserved interaction between different species of SAP05 with AtRpn10. Here, we have determined the crystal structure of the AtRpn10 complex with AY-WB or OY SAP05. Structure alignment revealed similar recognition patterns through sequences of two species SAP05 are poor homologous, which suggested phytoplasma may conduct resemble mode in plant infection. After docking the complex structure to the plant proteasome, we found that SAP05s location is near the ATPase central pore, which may be close enough to submit substrate with no need for ubiquitin in the degradation process.

biochemistry↗