Biology subjects

Liu, H.

Publications and source records attributed to Liu, H..

At least 415 records · Page 23Linked to original sources

bioRxiv2024

Topoisomerase I is an Evolutionarily Conserved Key Regulator for Satellite DNA Transcription

Repetitive satellite DNAs, divergent in nucleic-acid sequence and size across eukaryotes, provide a physical site for centromere assembly to orchestrate chromosome segregation during the cell cycle. These non-coding DNAs are transcribed by RNA polymerase (RNAP) II and the transcription has been shown to play a role in chromosome segregation, but a little is known about the regulation of centromeric transcription, especially in higher organisms with tandemly-repeated-DNA-sequence centromeres. Using RNA interference knockdown, chemical inhibition and AID/IAA degradation, we show that Topoisomerase I (TopI), not TopII, promotes the transcription of -satellite DNAs, the main type of satellite on centromeres in human cells. Mechanistically, TopI localizes to centromeres, binds RNAP II and facilitates RNAP II elongation on centromeres. Interestingly, in response to DNA double-stranded breaks (DSBs) induced by chemotherapy drugs or CRSPR/Cas9, -satellite transcription is dramatically stimulated in a DNA damage checkpoint-independent but TopI-dependent manner. These DSB-induced -satellite RNAs were predominantly derived from the -satellite high-order repeats of human centromeres and forms into strong speckles in the nucleus. Remarkably, TopI-dependent satellite transcription also exists in mouse 3T3 and Drosophila S2 cells and in Drosophila larval imaginal wing discs and tumor tissues. Altogether, our findings herein reveal an evolutionally conserved mechanism with TopI as a key player for the regulation of satellite transcription at both cellular and animal levels.

cell biology↗

bioRxiv2024

Heterogeneous local structures of the microtubule lattice revealed by cryo-ET and non-averaging analysis

Microtubule cytoskeletons play pivotal roles in various cellular processes, including cell division and locomotion, by dynamically changing their length and distribution in cells through tubulin polymerization/depolymerization. Recent structural studies have revealed the polymorphic lattice structure of microtubules closely correlate with the microtubule dynamics, but the studies were limited to averaged structures. To reveal the transient and localized structures, such as GTP-cap, we developed several non-averaging methods for cryogenic electron tomography to precisely measure the longitudinal spacing and helical twisting of individual microtubule lattices at the tubulin subunit level. Our analysis revealed that polymerizing and depolymerizing ends share a similar structure with regards to lattice spacing. The most distinctive property specific to the polymerizing plus end was left-handed twisting in the inter-dimer interface, suggesting that the twisting might accelerate fast polymerization at the plus ends. Our analysis uncovered the heterogeneity of native microtubules and will be indispensable for the study of microtubules dynamics under physiological contexts or during specific cellular events.

biophysics↗

bioRxiv2024

5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN{lozenge}arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

neuroscience↗

bioRxiv2024

Force-Enhanced Sensitive Detection of New DNA-Interactive Agents from Microorganisms at the Single-Molecule Level

The discovery of microbial-derived DNA-interacting agents, which hold broad therapeutic potential, is inherently challenging due to the limited sensitivity and specificity of conventional methodologies. Our study introduces a pioneering application of single-molecule stretching assay (SMSA) in natural product chemistry to identify DNA-intercalating agents directly from microbial cultures or extracts. We demonstrate that mechanical force can enhance sensitivity by increasing both the binding affinity Ka and the quantity of ligands bound. The changes induced by intercalators in the counter length and overstretching transition of dsDNA yield a distinctive and highly specific signature indicative of DNA intercalative binding, thereby enabling straightforward detection of DNA intercalators even in trace amounts from microbial cultures. This methodology eliminates the need for extensive large-scale fermentation and purification processes, thus offering a more streamlined approach to DNA-intercalating natural product discovery. By applying SMSA to 17 microorganisms, we identified two DNA intercalator-producing strains: Streptomyces tanashiensis and Talaromyces funiculosus. Subsequently, three DNA intercalators, namely medermycin, kalafungin, and ligustrone B, were isolated and characterized. Among them, medermycin and kalafungin showed significant inhibitory effects against HCT-116 cancer cells, with IC50 values of 52 {+/-} 6 nM and 70 {+/-} 7 nM, respectively.

biophysics↗

bioRxiv2024

MIPDB: A maize image-phenotype database with multi-angle and multi-time characteristics

Plant phenomics has become one of the most significant scientific fields in recent years. However, typical phenotyping procedures have low accuracy, low throughput, and are labor-intensive and time-consuming. Large-scale phenotypic collection equipment, on the other hand, is pricy, rigid, and inconvenient. The advancement of phenomics has been hampered by these restrictions. Lightweight picture collection equipment can now be used to capture plant phenotypic data thanks to the development of deep learning-based image identification. For the purpose of training the model, this approach needs high-quality annotated datasets. In this study, we used a handheld camera to gather multi-angle, multi-time series images and an unmanned aerial vehicle (UAV) to create a maize image phenotyping database (MIPDB). Over 30,000 high-resolution photos are available in the MIPDB, with 17,631 of those images having been carefully tagged with point-line method. The MIPDB can be accessed by the general public at http://phenomics.agis.org.cn. We anticipate that the availability of this superior dataset will stimulate a new revolution in crop breeding and advance deep learning-based phenomics research.

plant biology↗

bioRxiv2024

Cure or Curse? Simulation Indicates that Microbes Proliferate under Disinfection Measures in the Space Station

The long-term stay on the space station requirement poses a knotty issue about the stable hardware and reliable guarantee of astronauts health. Despite regular cleaning with wipes, microbes still proliferate in the space station. This study distilled three key factors--low-dose ionizing radiation, dilution and quaternary ammonium compound from the scenario. Species abundance and differential metabolites were applied to test their sole/combined influences on the three-simple-species microbial community succession. Mechanisms were built in mathematical models to generate the structural and behavior similarity. Results showed that LDIR, dilution and QAC, solely or jointly, could contribute to microbial proliferation. The synergy of disturbances might convert them from harmful factors to rewarding ones (e.g. the transformation of QAC into nutrients under LDIR), leading to this "Ecological Surprise". These results shed light on mechanisms driving microbial community succession in the space station and highlight the need for tailored biocontrol strategies in the specific environment.

ecology↗

bioRxiv2024

3D bioprinting of Liver Microenvironment Model Using Photocrosslinkable Decellularized Extracellular Matrix based Hydrogel

The liver, as one of the vital organs in the body, plays a crucial role in various bodily functions. Numerous factors can cause liver damage, that the sole remedy for severe liver conditions is the transplantation of healthy liver tissue. In response to the transplantation challenges, innovative approaches involving hydrogel-based technologies have emerged, leading to the creation of highly functionalized tissues. The development of three-dimensional printing and patterning of cell-laden biomaterial matrices offers promising advances for creating tissue-specific structures in tissue engineering and bioprinting. However, the matrix materials currently employed in bioprinting liver microtissue often fail to capture the complexity of the natural extracellular matrix (ECM), hindering their ability to restore innate cellular shapes and functions. Liver ECM-based hydrogels are increasingly recognized for their potential as biomimetic 3D cell culture systems that facilitate the exploration of liver disease, metabolism, and toxicity mechanisms. Yet, the conventional production of these hydrogels relies on slow thermal gelation processes, which restrict the manipulation of their mechanical characteristics. In this research, we introduce a novel approach with a functionalized photocrosslinkable liver decellularized extracellular matrix (dECM). By combining liver dECM methacrylate (LdECMMA) with gelatin methacrylate (GelMA), we achieved accelerated crosslinking under visible light irradiation and the ability to tune the mechanical, rheological, and physiological properties of the material. We encapsulated human hepatocellular carcinoma cells within an optimal concentration of the GelMA-LdECMMA hybrid hydrogel and examined cell proliferation and function over an extended period. The findings revealed that the GelMA-LdECMMA hybrid hydrogel enhances liver cell proliferation and function, holding significant promise for applications in drug screening and liver cancer metastasis research.

bioengineering↗

bioRxiv2024

Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive liver disease that encompasses a spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests that dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation through weight loss, but it is unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims to elucidate the intricate hepatic changes following DR, SG or sham surgery in rats fed a high-fat diet as a model of obesity-related MASLD, in comparison to a clinical cohort of patients undergoing SG. Single-cell and single-nuclei transcriptome analysis, spatial metabolomics, and immunohistochemistry revealed the liver landscape, while circulating biomarkers were measured in serum samples. Artificial intelligence (AI)-assisted image analysis characterized the spatial distribution of hepatocytes, myeloid cells and lymphocytes. In patients and experimental MASLD rats, SG improved BMI, circulating liver injury biomarkers and triglyceride levels. Both DR and SG attenuated liver steatosis and fibrosis in rats. Metabolism-related genes (Ppara, Cyp2e1 and Cyp7a1) were upregulated in hepatocytes upon DR and SG, while SG broadly upregulated lipid metabolism on cholangiocytes, monocytes, macrophages, and neutrophils. Furthermore, SG promoted myeloid cell accumulation in the liver not only ameliorating inflammation but activating liver repair processes. Regions with potent myeloid infiltration were marked with enhanced metabolic capacities upon SG. Additionally, a disruption of periportal hepatocyte functions was observed upon DR. In conclusion, this study indicates a dynamic cellular crosstalk in steatotic livers undergoing SG. Notably, PPAR- and gut-liver axis-related processes, and metabolically-active myeloid cell infiltration indicate intervention-related mechanisms supporting SG for the treatment of MASLD.

bioinformatics↗

bioRxiv2024

SHP-1 interacts with NFκB1 to inhibit its phosphorylation and nuclear translocation to suppress excessive bacterial inflammation

The protein tyrosine phosphatase SHP-1 is a key negative regulator in cancer by dephosphorylating multiple target molecules. Specially in the NF{kappa}B signaling, where NF{kappa}B1/Rela dimer translocate to the nucleus and activate target gene transcription, SHP-1 inhibits the phosphorylation of Rela, while its regulation on NF{kappa}B1 has been unknown, especially in pathogen-induced inflammation. Chinese tongue sole, a representative flatfish, has been widely used as a genomics and disease model. Using the teleost and cellular model, we revealed for the first time that SHP-1 inhibits NF{kappa}B1 phosphorylation and nuclear translocation by interacting with NF{kappa}B1, thereby suppressing NF{kappa}B signaling to inhibit bacterial inflammation. In addition, we showed that SHP-1 decreased mortality and alleviated histopathological deterioration, manifested in the inhibition of immune-related pathways and secretion of pro- inflammatory cytokines. Using cellular model, SHP-1 overexpression reduced macrophages M1 polarization, phagocytosis, and oxidative stress, while silencing SHP- 1 exhibited opposite effects. Our findings systematically dissect the functions of SHP- 1 and provide mechanistic insights into the control of inflammation-related diseases. TeaserSHP-1 help maintain the cellular and individual homeostasis by inhibiting the excessive inflammation and immunity via regulating the NF{kappa}B signaling.

immunology↗

bioRxiv2024

CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explored the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibited growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single- cell transcriptome levels. This mutation induced premature stem-like cell exhaustion, accelerated the maturation of GABAergic neurons, and disrupted neurodevelopmental and synaptic pathways. Additionally, it specifically hindered CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrored the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

molecular biology↗

bioRxiv2024

Caspase-8-mediated CYLD cleavage boots LPS-induced endotoxic shock.

Caspase-8, a pivotal protease intricately involved in various cellular signaling pathways related to cell death and inflammation, has been identified as a contributor to cytokine production during septic shock. However, the mechanisms governing this regulatory role remain enigmatic. In this study, we uncovered that mice harboring a specific mutation in CYLD at its D215 position (CyldD215A/D215A mutant mice), rendering CYLD resistant to caspase8 cleavage, exhibited marked protection against lethal endotoxic shock. Moreover, the removal of Cyld in Caspase8-/-Mlkl-/- mice restored their sensitivity to endotoxic shock, indicating Caspase8 promotes LPS-induced endotoxic shock by cleaving its substrate CYLD and maintaining CYLD stability confers resistance to endotoxic shock. Mechanistically, CYLD was found to catalyze the removal of LUBAC-mediated M1-linked ubiquitination of NF-kB p65 at K301/K303, thereby suppressing the nuclear translocation and activation of p65 for subsequent cytokines production. Notably, the cleaved N-terminal fragment of CYLD (named CP25) is secreted in a TRIF/Caspase8-dependent manner. Moreover, CP25 can be detected in the serum of septic mice, and its levels show a strong correlation with corresponding serum IL-1{beta}, suggesting its potential utility as an inflammatory biomarker. Overall, these findings highlight the significance of CYLD cleavage as a promising therapeutic target and diagnostic marker for endotoxic shock.

immunology↗

bioRxiv2024

Regulatory Functional Landscape of the HMX1 Gene for Normal Ear Development

Enhancers, through the combinatorial action of transcription factors (TFs), dictate both the spatial specificity and the levels of gene expression, and their aberrations can result in diseases. The association between HMX1 and its downstream enhancer with ear deformities has been previously documented. However, the pathogenic variations and molecular mechanisms underlying the bilateral constricted ear (BCE) malformations remain unclear. This study identifies a copy number variation (CNV) encompassing three enhancers that induces BCE. These enhancers, collectively termed the positional identity hierarchical enhancer cluster (PI-HEC), co-regulate spatiotemporal expression of the HMX1 gene in a coordinated and synergistic mode, each displaying unique activity-location-structure characteristics. A thorough exploration of this regulatory locus reveals that specific motif clusters within the PI-HEC variably modulate its activity and specificity, with the high mobility group (HMG) box combined with Coordinator and homeodomain (HD)-TFs notably influencing them respectively. Our findings based on various types of mouse models, reveal that both aberrant Hmx1 expression in the fibroblasts of the basal pinna, originating from neural crest cells, and ectopic expression in the distal pinna structures contribute to the abnormal development of the outer ear, including the cartilage, muscle, and epidermis tissues. This study deepens our understanding of mammalian ear morphogenesis and sheds light on the complexity of gene expression regulation by enhancers and specific sequence motifs.

developmental biology↗

bioRxiv2024

Hepatitis E virus infection upregulates ING5 expression in vitro and vivo

Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individual infected by HEV is prone to chronic hepatitis and increases the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor gene, is low expressed in cancer tumor or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study acute and chronic HEV animal models were employed to explore the interaction between ING5 and HEV. Notably, the expression of ING5 was significantly increased both in the liver of acute HEV infected BALB/c mice and chronic HEV infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression was further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulated ING5 expression in vivo and in vitro, bearing significant implications in further understanding the pathogenic mechanism of HEV infection.

microbiology↗

bioRxiv2024

Rapid High-Throughput Isolation and purification of Chicken Myoblasts Based on Deterministic Lateral Displacement Microfluidic Chips

Myoblasts are defined as stem cells containing skeletal muscle cell precursors. However, there are some challenges associated with the purification of myoblast samples, including long culture times and ease of bacterial contamination. In this study, we propose a microfluidic myoblast cell enrichment and purification platform based on the principle of deterministic lateral displacement (DLD). To achieve this, we designed a DLD chip with three outlets and tested it on 11-day-old Wenchang chicken pectoral muscle tissue. A cell suspension was prepared using the collagenase method, pretreated, and then passed into the designed DLD chip for myoblast enrichment and purification. In this study, the number of myoblasts and the diameter of myoblasts increased slowly before E9, and the diameter of myofibers decreased and the number of myofibers increased rapidly after E9. The period when the number of muscle fibers is highest is E12, and the period when the diameter of muscle fibers increases again after the lowest point is also E12. After E12, the diameter of the muscle fibers increased and the number of muscle fibers decreased. At E12, myoblasts clustered and fused, and the proliferation of myoblasts was greatly reduced. E12 is both intact myoblasts and the most vigorous proliferation period, so the best time to determine isolation is E12. We attained a myoblast cell recovery rate of 80%, a target outlet collection purity of 99%, and a chip throughput of 50 m/min. This study provides a novel and effective method for the isolation and purification of skeletal muscle myoblasts.

cell biology↗

bioRxiv2024

Mutating the arginine residue within the FRNK motif of HC-Pro yield highly attenuated strains that confer complete cross protection against telosma mosaic virus (TelMV) in passion fruit (Passiflora edulis)

Telosma mosaic virus (TelMV, Potyvirus, Potyviridae) is an emerging viral pathogen causing a major global threat to passion fruit plantations. However, an efficient strategy for controlling such viruses is not yet available. Cross protection is a phenomenon in which pre-infection of a plant with one virus prevents or delays superinfection with the same or closely related virus. HC-Pro is the potyviral encoded multifunctional protein involved in several steps of viral infection, including multiplication, movement, transmission and RNA silencing suppression. The main hypothesis we tested in this study was whether it is possible to generate attenuated viral strains capable of conferring protection against severe TelMV infection by manipulating the HC-Pro gene. By introducing point mutation into the potyviral conserved motif FRNK of HC-Pro, we have successfully obtained three highly attenuated mutants of TelMV (R181K, R181D and R181E, respectively) that can systemically infect passion fruit plants without any noticeable symptoms. Importantly, these mutants confer complete protection against subsequent infection of severe recombinant virus TelMV-GFP, evidenced by no detection of viral RNA or protein of the superinfection virus in the systemic leaves of passion fruit plants in both early and late stages. Lastly, we demonstrated that the HC-Pros harbored by the highly attenuated mutants exhibited reduced RNA silencing suppression activity in Nicotiana benthamiana leaves. Altogether, this study provides the first demonstration of the generation of highly attenuated strains for TelMV and highlights key amino acid residue involved in complete cross protection against TelMV, opening a new avenue to fight TelMV in the field.

pathology↗

bioRxiv2024

GGCX promotes Eurasian avian-like H1N1 swine influenza virus adaption to interspecies receptor binding

The Eurasian avian-like (EA) H1N1 swine influenza virus (SIV) possesses the capacity to instigate the next influenza pandemic, owing to its heightened affinity for the human-type -2,6 sialic acid (SA) receptor. Nevertheless, the molecular mechanisms underlying the switch in receptor binding preferences of EA H1N1 SIV remain elusive. In this study, we conducted a comprehensive genome-wide CRISPR/Cas9 knockout screen utilizing EA H1N1 SIV in porcine kidney cells. Knocking out the enzyme gamma glutamyl carboxylase (GGCX) reduced virus replication in vitro and in vivo by inhibiting the carboxylation modification of viral haemagglutinin (HA) and the adhesion of progeny viruses, ultimately impeding the replication of EA H1N1 SIV. Furthermore, GGCX was revealed to be the determinant of the D225E substitution of EA H1N1 SIV, and GGCX-medicated carboxylation modification of HA 225E contributed to the receptor binding adaption of EA H1N1 SIV to the -2,6 SA receptor. Taken together, our CRISPR screen has elucidated a novel function of GGCX in the support of EA H1N1 SIV adaption for binding to -2,6 SA receptor. Consequently, GGCX emerges as a prospective antiviral target against the infection and transmission of EA H1H1 SIV.

microbiology↗

bioRxiv2024

EHMT2 Inactivation in Pancreatic Epithelial Cells Shapes the Transcriptional Landscape and Inflammation Response of the Whole Pancreas

The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that EHMT2 inactivation alters growth and immune gene expression networks, antagonizing KRAS-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of EHMT2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from EHMT2 conditional knockout animals (EHMT2fl/fl) targeted to the exocrine pancreatic epithelial cells (Pdx1-Cre and P48Cre/+), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the EHMT2fl/flpancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The EHMT2fl/fl pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional EHMT2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific EHMT2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the EHMT2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.

cancer biology↗

bioRxiv2024

Protein disulfide isomerase disassembles stress granules and blocks cytoplasmic aggregation of TDP-43 in ALS

Cytoplasmic aggregation of the transactive response DNA-binding protein-43 (TDP-43) in neurons, a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, has been found in some Alzheimers patients. Protein disulfide isomerase (PDI) functions as both an enzyme and a molecular chaperone to correct or eliminate misfolded proteins under pathological conditions. Here, we report that TDP-43 is mislocalized to the cytoplasm and colocalizes with PDI in the brain and spinal cord of two ALS patients and the brain of six Alzheimers patients compared to controls. TDP-43 selectively recruits wild-type PDI into its phase-separated condensate, which in turn slows down in vitro liquid-liquid phase separation of TDP-43, shifting the equilibrium phase boundary to higher protein concentrations. Importantly, wild-type PDI decreases oxidative stress-induced interaction between TDP-43 and G3BP1 to disassemble stress granules containing TDP-43 in neuronal cells. Wild-type PDI blocks the oxidative stress-induced mislocalization of TDP-43 to the cytoplasm, and blocks subsequent pathological phosphorylation and aggregation of TDP-43. We demonstrate that under pathological stress conditions, wild-type PDI disassembles stress granules, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppresses mitochondrial damage and TDP-43 toxicity. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS patients and some Alzheimers patients. TeaserPDI disassembles SGs, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppress TDP-43 toxicity in ALS.

biochemistry↗