Biology subjects

Shi, Y.

Publications and source records attributed to Shi, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2024

Newly discovered and conserved role of IgM against viral infection in an early vertebrate

IgM emerged in jawed vertebrates 500 Mya and remains the most evolutionarily conserved antibody class. However, despite extensive studies on IgM as an ancient antiviral weapon in warm-blooded vertebrates, its role and mechanisms in combating viral infections in early vertebrates remain poorly understood. Here, we found that significant virus-specific sIgM titers were generated in serum and gut mucus of teleost fish that survived infection, and fish lacking sIgM were more susceptible to viral infection. These results challenge the paradigm that IgM and IgT are specialized to systemic and mucosal immunity, respectively. More crucially, our study provides further insight into the role of sIgM in viral neutralization and firstly clarified the mechanism through which teleost sIgM blocks viral infection by directly targeting viral particles. From an evolutionary perspective, our findings indicate that sIgM in both primitive and modern vertebrates follow conserved principles in the development of specialized antiviral immunity.

immunology↗

bioRxiv2024

PSTP: Decoding Latent Sequence Grammar through Transfer Learning and Attention for Protein Phase Separation

Phase separation (PS) is essential in various biological processes, necessitating high-accuracy predictive algorithms for studying numerous uncharacterized sequences, and accelerating experimental validation. However, many recent prediction methods face challenges in generalizability due to their reliance on engineered features. Furthermore, accurately identifying protein regions involved in PS remains challenging. To address this, we propose PSTP, a model employing a dual-language model embedding strategy and a lightweight attention module. The attention layer enables reliable residue-level phase separation predictions, identifying 84% of PS regions in PhaSePro and substantially improving correlation coefficient compared to existing models. PSTP also demonstrates robust performance in predicting PS propensity across various types of PS proteins and shows potential for predicting artificial proteins. By analyzing 160,000+ variants, PSTP characterizes the link between the incidence of pathogenic variants and residue-level PS propensities. PSTPs predictive power and broad applicability make it a valuable tool for understanding biomolecular condensates and disease mechanisms.

bioinformatics↗

bioRxiv2024

Novel symbionts reveal amoebae as significant hosts for environmental chlamydiae

Chlamydiae represent a diverse group of obligate intracellular bacteria with elusive hosts in environmental settings. This study used one of the largest collections of wild amoebae (Dictyostelium discoideum and D. giganteum, 106 clones) collected over the past two decades to screen for novel environmental chlamydiae. We found that novel environmental chlamydiae are prevalent in two wild Dictyostelium species and assembled 42 novel chlamydiae metagenome-assembled genomes (MAGs). The MAGs represent three chlamydiae species previously only reported using 16S sequencing. Their genomes are divergent enough from other species to warrant placing them in two new genera (tentatively called Ca. Dictychlamydia sp. LF1, Ca. Dictychlamydia sp. LF2, and Ca. Feichlamydia sp. LF3). In addition, these chlamydiae species show strong host specificity with two Dictyostelium amoeba hosts, except one amoeba sample. Ca. Dictychlamydia sp. LF1 and Ca. Feichlamydia sp. LF3 was exclusively observed in D. discoideum, while Ca. Dictychlamydia sp. LF2 was found only in D. giganteum. Phylogenetic and comparative genomic analyses suggest that all three chlamydiae are close to arthropod-associated chlamydiae and likely have some intermediate characteristics between previously reported amoeba-associated and vertebrate-associated chlamydiae. This study significantly broadens our understanding of the chlamydial host range and underscores the role of amoebae as vital hosts for environmental chlamydiae.

microbiology↗

bioRxiv2024

Epigenetic control of Topoisomerase 1 activity presents a cancer vulnerability

DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from aberrant TOP1 activity remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. By visualizing transcription-induced topological stress in single cells, we find that macroH2A1.1 facilitates PAR-dependent recruitment of the TOP1cc repair effector XRCC1 to protect from ssDNA damage. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

molecular biology↗

bioRxiv2024

Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9

Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.

immunology↗

bioRxiv2024

Temporal multi-modal single-cell analyses reveal dynamic interactions of CAR-T cells with glioblastoma and targeting of antigen-negative neoplastic cells

CAR-T therapy is a promising new immunotherapy for cancers, but its efficacy for solid tumors requires improvement. A detailed understanding of the interplay between solid tumors and CAR-T cells is critical. Here we report temporal, multi-modal, single-cell profiling of patient-derived glioblastoma organoids with CAR-T treatment. We found that all tumor cell types responded to CAR-T cell activation and contributed to an initially anti-tumor, but subsequently pro-tumor and immune-inhibitory microenvironment, accompanied by CAR-T cell exhaustion. Unexpectedly, CAR-T treatment attenuated glioma stem-like states of both antigen-positive and antigen-negative neoplastic cells and reduced their proliferation via diffusible factors, including IFN{gamma}. Analysis of samples from additional patients, including those in clinical trials, supported these findings. Our study reveals the dynamic interplay among different tumor cells and T cells in adaptive responses to immunotherapy and identifies previously unappreciated benefits of CAR-T therapy directly on antigen-negative neoplastic cells that may be leveraged to enhance therapeutic efficacy.

cancer biology↗

bioRxiv2024

Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection

cGMP signal-activated ookinete gliding is essential for mosquito midgut infection of Plasmodium in malaria transmission. During ookinete development, cGMP synthesizer GC{beta} polarizes to a unique localization <ookinete extrados site= (OES) until ookinete maturation and activates cGMP signaling for initiating parasite motility. However, the mechanism underlying GC{beta} translocation from cytosol to OES remains elusive. Here, we used protein proximity labeling to search the GC{beta}-interacting proteins in ookinetes of the rodent malaria parasite P. yoelii, and found the top hit Sir2A, a NAD+-dependent sirtuin family deacetylase. Sir2A interacts with GC{beta} throughout ookinete development. In mature ookinetes, Sir2A co-localizes with GC{beta} at OES in a mutually dependent manner. Parasites lacking Sir2A lose GC{beta} localization at OES, ookinete gliding, and mosquito infection, phenocopying GC{beta} deficiency. GC{beta} is acetylated at gametocytes but is deacetylated by Sir2A for OES localization at mature ookinetes. We further demonstrated that the level of NAD+, an essential co-substrate for sirtuin, increases during the ookinete development. The NAD+ at its maximal level until ookinete maturation promotes Sir2A-catalyzed GC{beta} deacetylation, ensuring GC{beta} localization at OES. This study highlights the spatiotemporal coordination of cytosolic NAD+ level and NAD+-dependent Sir2A in regulating GC{beta} deacetylation and dynamic localization for Plasmodium ookinete gliding.

microbiology↗

bioRxiv2024

Deep learning for classifying neuronal morphologies: combining topological data analysis and graph neural networks

Neuronal shape determines how neurons process and integrate information, yet a consistent and objective classification of neuronal morphologies remains elusive. Current approaches rely heavily on subjective expert views or on predefined features, limiting reproducibility and interpretability. Here, we present an interpretable deep learning framework that unifies topological data analysis, graph neural networks, and traditional morphometrics to classify neuronal morphologies objectively and transparently. Our framework compares complementary mathematical representations of neurons to capture geometric, topological, and graph-structural information. Then it benchmarks their performance against expert-labeled datasets. We show that topology- and graph-based models achieve accuracies comparable to human experts, revealing that both global branching invariants and local connectivity patterns are essential to define morphological cell types. Using explainable artificial intelligence methods, we identify structural features driving each classification decision, bridging computational and neuroanatomical interpretations. This open source and reproducible approach provides a foundation for scalable, interpretable and biologically meaningful neuronal taxonomy, enabling consistent comparisons between data sets and species.

neuroscience↗

bioRxiv2024

53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR)

Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Pol-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.

molecular biology↗

bioRxiv2024

The role of PilU in the surface behaviors of Pseudomonas aeruginosa

In Pseudomonas aeruginosa, the dynamic activity of type IV pilus (TFP) is essential for various bacterial behaviors. While PilU is considered a homolog of the TFP disassembling motor PilT, its specific roles remain unclear. Using pilus visualization and single-cell tracking techniques, we characterized TFP dynamics and surface behaviors in wild-type and {Delta}pilU mutants. We found that {Delta}pilU cells displayed increased TFP numbers but reduced cell movement and delayed microcolony formation. Interestingly, beyond affecting the twitching motility, {Delta}pilU cells formed a thick multilayered colony edge on semi-solid surfaces, slowing colony expansion. Cell-cell collision responses changed from touch-turn dominance in wild-type to touch-upright dominance in {Delta}pilU, affecting colony morphology and expansion. These findings expand our understanding of PilUs physiological roles and provide potential targets for developing strategies to control P. aeruginosa biofilm formation and virulence. IMPORTANCEThe dynamic function of TFP can help cells to search appropriate spatial positions and perceive external environments, and is crucial for a variety of cell behaviors including cell movement, pathogenesis, natural transformation and biofilm formation. Beyond the current picture of PilU in generating high retraction forces through a PilT-dependent manner, this study revealed more roles of PilU in cell surface behaviors including single cell behavior like twitching and multicellular behaviors such as microcolony formation and colony expansion. These findings expand our understanding on the physiological roles of PilU in the surface behaviors of P. aeruginosa, and provide us insight in developing TFP-based methods to control the pathogenicity and biofilm formation of P. aeruginosa.

microbiology↗

bioRxiv2024

Toxoplasma gondii transcription factor AP2XII-8: a key regulator of G1 phase progression and parasite division

The apicomplexan parasite Toxoplasma gondii can infect humans and virtually all warm-blooded animals worldwide, posing a significant threat to public health and being of veterinary importance. Acute infections are characterized by the fast replication of tachyzoites inside host cells. During this fast amplification process, gene expression is highly regulated by a series of regulatory networks. The G1 phase, which is usually conserved across species, is responsible for preparing the materials necessary for the next replicating cell cycle; however, few regulators have been identified at this stage. Here, we functionally characterized the C/G1 phase-expressed ApiAP2 transcription factor, TgAP2XII-8, in T. gondii tachyzoites. Conditional knockdown of TgAP2XII-8 leads to significant growth defects and asexual division disorders. Additionally, parasite cell cycle progression was disrupted following TgAP2XII-8 depletion, characterized by G1 phase arrest. RNA-seq and CUT&Tag experiments revealed that TgAP2XII-8 acts as an activator of ribosomal proteins expressed in the G1 phase. Moreover, TgAP2XII-8 binds to a specific DNA motif ([T/C]GCATGCA), which is abundant and conserved in the intergenic region of several other apicomplexans, possibly suggesting a broad and conserved role for this ApiAP2 in the Phylum of Apicomplexa. Our study reveals that TgAP2XII-8 acts as a critical C/G1 phase regulator, orchestrating the cell cycle in T. gondii tachyzoites. This study contributes to a broader understanding of the complexity of the parasites cell cycle and its key regulators.

microbiology↗

bioRxiv2024

Molecular and spatiotemporal characterization of cells in murine atherosclerotic plaques

ObjectiveSingle-cell technologies have revolutionized our understanding of the phenotypic and transcriptional diversity of aortic leukocytes in atherosclerotic humans and mice. However, enzymatically dissociated tissues lose the spatial context of plaque cells in situ. Here we utilized imaging mass cytometry (IMC) combining with single-cell RNA sequencing (scRNA-seq) to characterize the spatial distribution dynamics, phenotypic transitions, metabolic and functional phenotypes, and the intercellular interaction networks of plaque cells during atherosclerotic progression. Additionally, the dynamic immune landscape of circulating leukocytes associated with atherosclerosis was characterized using cytometry of time of flight (CyTOF). Approach and ResultsA highly multiplexed IMC panel with 33 metal-conjugated antibodies was designed to generate 11 highly multiplexed histology images of aortic root tissues from ApoE-/- mice on high-fat diet at different stage of atherosclerosis. Using histoCAT, we identified 8 principal cell subtypes with distinct phenotypic and geographic dynamics. Furthermore, IMC-defined cell subsets partially corresponded to scRNA-seq-annotated aortic cell subtypes, including 4 macrophage subsets, neutrophils, smooth muscle cells (SMCs) and SMC-derived SEMs (Stem cell, endothelial cell and macrophage-like cell). Activation of inflammatory pathways, increased oxidative phosphorylation and augmented osteoclast differentiation were observed in macrophage populations, SMCs and SEMs from an early stage to advanced stage of atherosclerosis. Notably, cell neighborhood analysis by IMC uncovered multifaceted cell-cell interactions within the plaque, in particular in neutrophil-mediated interactions with smooth muscle cells and macrophages, which were confirmed by ligand-receptor interactions based on scRNA-seq data. Additionally, characterization of the peripheral immune cells by CyTOF revealed an increased ratio of myeloid cells to lymphocytes, and certain neutrophil and monocyte subpopulations also exhibited enhanced lipid metabolism and glycolysis as well as activated inflammatory signaling. ConclusionThis study provides a dynamic spatiotemporal landscape of atherosclerotic lesions and peripheral leukocytes. The new information based on IMC may help understand atherosclerotic pathology and develop novel therapeutic strategies.

pathology↗

bioRxiv2024

Opposing actomyosin pools generate cortical flows that establish epithelial polarity

Epithelial cell polarity, defined by distinct apical and basolateral domains, is fundamental for animal embryonic development and organ function. During organogenesis, epithelia often develop from unpolarized precursor cells. How mammalian epithelial cells establish polarity de novo from an initially unpolarized state has remained unclear, in part due to an inability to observe this process in real time in non-transformed cellular systems. Here, we leverage recent advances in 3D spheroid culture of mouse embryonic stem cells, fluorescent protein knock-in and live imaging techniques to study the process of epithelial polarity establishment. We show that apical myosin activity, regulated by Myosin Light Chain Kinase (MLCK), is crucial for the establishment and maintenance of epithelial polarity. Actomyosin cortical flows transport ZO-1, a tight junction component that interacts with apical polarity proteins, to establish the apical membrane. A second pool of myosin, regulated by Rho kinase, localizes basally and balances apically directed flow. Our result imply that epithelial polarity emerges as a consequence of actomyosin-driven cytoskeletal rearrangements.

cell biology↗

bioRxiv2024

Novel tau filament folds in individuals with MAPT mutations P301L and P301T

Mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological MAPT variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common MAPT mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Picks disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.

neuroscience↗

bioRxiv2024

A STAT3 Degrader Demonstrates Pre-clinical Efficacy in Venetoclax resistant Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that continues to have poor prognosis despite recent therapeutic advances. Venetoclax (Ven), a BCL2-inhibitor has shown a high response rate in AML; however, relapse is invariable due to mitochondrial dysregulation that includes upregulation of the antiapoptotic protein MCL1, a central mechanism of Ven resistance (Ven-res). We have previously demonstrated that the transcription factor STAT3 is upregulated in AML hematopoietic stem and progenitor cells (HSPCs) and can be effectively targeted to induce apoptosis of these aberrant cells. We now show that overexpression of STAT3 alone is sufficient to initiate a strong AML phenotype in a transgenic murine model. Phospho-proteomic data from Ven treated AML patients show a strong correlation of high total STAT3 and phospho-STAT3 [both p-STAT3(Y705) and p-STAT3(S727)] expression with worse survival and reduced remission duration. Additionally, significant upregulation of STAT3 was observed in Ven-res cell lines, in vivo models and primary patient samples. A novel and specific degrader of STAT3 demonstrated targeted reduction of total STAT3 and resulting inhibition of its active p-STAT3(Y705) and p-STAT3(S727) forms. Treatment with the STAT3 degrader induced apoptosis in parental and Ven-res AML cell lines and decreased mitochondrial depolarisation, and thereby dependency on MCL1 in Ven-res AML cell line, as observed by BH3 profiling assay. STAT3 degrader treatment also enhanced differentiation of myeloid and erythroid colonies in Ven-res peripheral blood mononuclear cells (PBMNCs). Upregulation of p-STAT3(S727) was also associated with pronounced mitochondrial structural and functional dysfunction in Ven-res cell lines, that were restored by STAT3 degradation. Treatment with a clinical-stage STAT3 degrader, KT-333 resulted in a significant reduction in STAT3 and MCL1 protein levels within two weeks of treatment in a cell derived xenograft model of Ven-res AML. Additionally, this treatment significant improvement in the survival of a Ven-res patient-derived xenograft in-vivo study. Degradation of STAT3 resulting in downregulation of MCL1 and improvements in global mitochondrial dysfunction suggests a novel mechanism of overcoming Ven-res in AML. Statement of PurposeFive-year survival from AML is dismal at 30%. Our prior research demonstrated STAT3 over-expression in AML HSPCs to be associated with inferior survival. We now explore STAT3 over-expression in Ven-res AML, explain STAT3 mediated mitochondrial perturbations and describe a novel therapeutic strategy, STAT3 degradation to overcome Ven-res.

cancer biology↗

bioRxiv2024

A nuclear RNA degradation code for eukaryotic transcriptome surveillance

The RNA exosome plays critical roles in eukaryotic RNA degradation, but it remains unclear how the exosome specifically recognizes its targets. The PAXT connection is an adaptor that recruits the exosome to polyadenylated RNAs in the nucleus, especially transcripts polyadenylated at intronic poly(A) sites. Here we show that PAXT-mediated RNA degradation is induced by the combination of a 5' splice site and a poly(A) junction, but not by either sequence alone. These sequences are bound by U1 snRNP and cleavage/polyadenylation factors, which in turn cooperatively recruit PAXT. As the 5' splice site-poly(A) junction combination is typically not found on correctly processed full-length RNAs, we propose that it functions as a "nuclear RNA degradation code" (NRDC). Importantly, disease-associated single nucleotide polymorphisms that create novel 5' splice sites in 3' untranslated regions can induce aberrant mRNA degradation via the NRDC mechanism. Together our study identified the first NRDC, revealed its recognition mechanism, and characterized its role in human diseases.

molecular biology↗

bioRxiv2024

dsRNAEngineer: a web-based tool of comprehensive dsRNA design for pest control

RNA interference (RNAi) is a form of gene silencing triggered by double-stranded RNA (dsRNA) that operates in all eukaryotic organisms, including insects, mites, nematodes and fungi. In the last two decades, many dsRNAs have been synthesized to silence the target genes for exploration of the underlying function in these pests. Some of them are lethal to pests or inhibit the growth of the pest population, leading to a new concept of pesticides. The generation of these environment-friendly pesticides requires precise in silico design of dsRNA molecules that are specific to target pests but do not target non-pest organisms. Current efforts for dsRNA design are mostly focused on gene sequence level, lacking comprehensive analysis of RNAi-based mode-of-action at the whole transcriptome level of given species, causing low efficiency and imprecise dsRNA target exploration. To address these limitations, we have created dsRNAEngineer, a publicly available online tool that allows a comprehensive and rational dsRNA design, incorporating hundreds of pests and non-pests transcriptomes. Developed functionalities include screen-target (screen conserved genes for co-targets of various pest species), on-target, off-target, and multi-target to generate optimal dsRNA for precise pest control. dsRNAEngineer is available at https://dsrna-engineer.cn/. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/604585v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@9ee7fdorg.highwire.dtl.DTLVardef@90b015org.highwire.dtl.DTLVardef@11857eborg.highwire.dtl.DTLVardef@1340f18_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

PA2gamma promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP

Proteasome activator 28{gamma} (PA28{gamma}) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as main research model, we discovered that PA28{gamma} interacted with complement 1q binding protein (C1QBP), which is dependent on the N-terminus of C1QBP rather than the known functional domain (amino acids 168-213). Notably, we found that PA28{gamma} enhances C1QBP protein stability in OSCC. Functionally, PA28{gamma} contributes to the malignant progression of OSCC by affecting mitochondrial morphology and oxidative phosphorylation (OXPHOS) through C1QBP in vitro and vivo. Mechanically, PA28{gamma} upregulates the expression of optic atrophy 1 (OPA1), mitofusin 1 (MFN1), mitofusin 2 (MFN2), and the mitochondrial respiratory complex via C1QBP. Moreover, in a clinical cohort of OSCC patients, PA28{gamma} was positively correlated with C1QBP expression and negatively correlated with prognosis. Therefore, C1QBP represents a potential therapeutic target for cancer treatment and prognosis.

cancer biology↗