[Weekly News] CRISPR Library Screening Uncovers ALCAM as a Novel Molecular Target for Human Adenovirus B
CRISPR/Cas technology is a revolutionary tool in modern biological sciences, with applications spanning medicine, agriculture, environmental conservation, and more. New findings and case studies continue to emerge across these fields. Our‘CRISPR Weekly News’column brings you the latest research and industry updates. Here's a brief summary of the past week's highlights:
I. Research Updates
1. Title: Deciphering the role of the MALT1–RC3H1 axis in regulating GPX4 protein stability
Journal: PANS (Impact Factor: 9.4)
Original Link:https://doi.org/10.1073/pnas.2419625121
Ferroptosis, a form of cell death caused by dysregulated iron metabolism, relies on GPX4 as a key antioxidant enzyme to neutralize lipid hydroperoxides. However, the regulation of GPX4 remains unclear. Researchers from China employed CRISPR library screening to investigate GPX4 regulation and identified how MALT1 protects GPX4 by cleaving the E3 ubiquitin ligase RC3H1, preventing ubiquitin-mediated degradation. Pharmacological inhibition of MALT1 using MI-2 induced ferroptosis and showed synergistic effects when combined with sorafenib or regorafenib in multiple cancer types, including liver, thyroid, kidney, and colorectal cancers. This study not only advances the understanding of GPX4 regulation but also offers a novel therapeutic strategy for liver cancer treatment.
2. Title: ALCAM is an entry factor for severe community acquired Pneumonia-associated Human adenovirus species B
Journal: Nature Communications (Impact Factor: 14.7)
Original Link:https://doi.org/10.1038/s41467-024-55261-3
ALCAM has been identified as a critical protein in severe community-acquired pneumonia (SCAP) caused by human adenovirus species B (HAdV-B). CRISPR screening revealed host factors influencing HAdV-B infection, including the known receptor DSG-2 and the novel factor ALCAM. Further studies showed that ALCAM facilitates viral internalization, promoting HAdV-B infection. Transcriptomic analysis of human blood samples indicated higher ALCAM expression in SCAP patients infected with HAdV-B compared to others. This discovery positions ALCAM as an entry factor for HAdV-B and a promising molecular target for developing new therapeutic strategies.
3. Title: Chicken genome-wide CRISPR library screen identifies potential candidates associated with Avian influenza virus infection
Journal: International Journal of Biological Macromolecules (Impact Factor: 7.7)
Original Link:https://doi.org/10.1016/j.ijbiomac.2024.139267
A groundbreaking study in avian influenza virus (AIV) research offers hope for poultry industries and public health. Researchers developed a comprehensive chicken genome CRISPR/Cas9 knockout library and conducted a genome-wide screen in chicken fibroblasts (DF-1 cells). After multiple rounds of survival selection under AIV infection, they identified 706 potential genes, including 107 previously associated with AIV infection. These genes are involved in processes like ubiquitin pathways, RNA transport, and endocytosis. Notably, 18 novel targets were linked to AIV-induced cell death, and 8 genes were directly involved in AIV proliferation. Key findings include RNF2 as a negative regulator of interferon-stimulated genes (ISGs), DCP1A influencing AIV-related gene expression, and CREB3L3 potentially regulating membrane cholesterol levels during AIV entry. This study not only identifies 599 chicken-derived genes involved in AIV infection but also lays the groundwork for understanding AIV mechanisms in avian cells.
1.Title: A CRISPR/Cas12a-based direct transverse relaxation time biosensor via hydrogel sol-gel transition for Salmonella detection
Journal: Food Chemistry (Impact Factor: 8.5)
Original Link:https://doi.org/10.1016/j.foodchem.2024.142693
In food safety detection, a breakthrough has been made with a magnetic relaxation switching (MRS) biosensor based on hydrogel sol-gel transition and the CRISPR/Cas12a system. This biosensor leverages alkaline phosphatase (ALP) bound to streptavidin via biotin-modified DNA captured on magnetic nanoparticles (MNPs). The enzymatic reaction creates an acidic environment that releases Ca²⁺, triggering the alginate sol-to-hydrogel transition. Salmonella presence activates the trans-cleavage activity of CRISPR/Cas12a, disrupting ALP capture and sol-gel transition. By measuring transverse relaxation time (T2), the biosensor achieves sensitive Salmonella detection with a limit of 158 CFU/mL. Unlike traditional MRS sensors that indirectly generate T2 signals, this novel biosensor directly alters water molecule states, overcoming limitations of previous methods. This innovation offers a new perspective for applying MRS technology in food safety analysis.
2.Title: Ligation-recognition triggered RPA-Cas12a cis-cleavage fluorogenic RNA aptamer for one-pot and label-free detection of MicroRNA in breast cancer
Journal: Biosensors and Bioelectronics (Impact Factor: 10.7)
Original Link:https://doi.org/10.1016/j.bios.2024.117106
Researchers from China have developed a novel ligation-recognition triggered recombinase polymerase amplification (RPA)-CRISPR/Cas12a cis-cleavage (LRPA-CRISPR) fluorescent biosensor for sensitive, specific, and label-free detection of microRNAs (miRNAs). The technique utilizes pre-designed double-stranded DNA amplicons formed through ligation recognition and amplified by the RPA system. The exponential ligation recognition of miRNA-21 triggers RPA, leveraging Cas12a’s cis-cleavage mechanism and functional RNA aptamer (Mango RNA) transcription for signal output. The method requires only 40 minutes and achieves a detection limit of 3.43 aM for miRNA-21. It is applicable to serum and cell samples, demonstrating significant potential for diagnosing breast cancer biomarkers.
iii. Other CRISPR-Related Research
1. Title: The histone H3.3 K27M mutation suppresses Ser31phosphorylation and mitotic fidelity, which can directly drive gliomagenesis
Journal: Current Biology (Impact Factor: 8.1)
Original Link:https://doi.org/10.1016/j.cub.2024.11.035
A new study highlights the pivotal role of Ser31 phosphorylation, a specific site on the histone H3.3 variant, in chromosome segregation and cell cycle regulation. The H3.3 K27M mutation, found in approximately 80% of pediatric diffuse midline gliomas, is associated with reduced Ser31 phosphorylation and increased chromosome missegregation. Expression of the H3.3 K27M mutant in normal diploid cells caused elevated chromosomal mismatch and failure of G1 arrest. Similarly, non-phosphorylatable S31A mutants led to chromosomal mismatches, whereas dual K27M and phosphomimetic S31E mutations restored mitotic fidelity and p53-mediated responses to chromosomal errors. CRISPR-mediated reversal of the K27M mutation to wild-type (WT) restored Ser31 phosphorylation and reduced chromosomal mismatches. This study underscores the impact of the H3.3 K27M mutation on Ser31 phosphorylation and its far-reaching implications for chromosome segregation and cell cycle regulation, offering new insights into glioma treatment strategies.
2. Title: Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function
Journal: Neoplasia (Impact Factor: 6.3)
Original Link:https://doi.org/10.1016/j.neo.2024.101117
Published in Neoplasia, this study investigates how Galectin-3 (Gal-3), secreted by triple-negative breast cancer (TNBC) cells, modulates T cell function. Using CRISPR/Cas9 gene editing, researchers generated Gal-3-deficient clones and studied their interactions with T cells in vitro and in vivo. The findings revealed that Gal-3-deficient tumors exhibited slower growth in mice following PBMC transplantation, while Gal-3-positive tumors maintained growth and showed increased infiltration of regulatory T cells (CD4/FoxP3+). Moreover, Gal-3 was implicated in mitochondrial dysfunction and reduced oxidative phosphorylation gene expression in T cells from TNBC patients, leading to elevated reactive oxygen species (ROS) levels and T cell exhaustion in CD8+ T cells. These results provide valuable insights into the immunomodulatory mechanisms within the TNBC tumor microenvironment and may inform the development of novel immunotherapeutic strategies.
II. Industry News
1. GEMMA Biotherapeutics (GEMMABio), a pioneering therapeutic company founded by gene therapy expert Dr. Jim Wilson, announced the completion of a $34 million seed funding round. The financing was co-led by Double Point Ventures, Bioluminescence Ventures, and Earlybird Venture Capital, with participation from Savanne Life Sciences. The funds will support GEMMABio’s operational expansion and innovative gene therapy programs. The company is dedicated to advancing gene therapy research and delivering life-changing therapies to patients worldwide. This funding will accelerate GEMMABio’s efforts to bring transformative treatments to those in need globally.
2. CSPC Pharmaceutical Group announced that its self-developed Class 1 chemical new drug, SYH2062 injection—a dual-strand small interfering RNA (siRNA) therapy—has received approval from China’s National Medical Products Administration for clinical trials. The innovative drug uses galactosamine (GalNAc)-conjugated delivery technology to target and inhibit angiotensinogen (AGT), offering a novel treatment for hypertension. This milestone marks a significant breakthrough for CSPC in the gene therapy field, bringing new hope to patients with hypertension.
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