EMBO Reports, Год журнала: 2022, Номер 23(11)
Опубликована: Сен. 20, 2022
Язык: Английский
EMBO Reports, Год журнала: 2022, Номер 23(11)
Опубликована: Сен. 20, 2022
Язык: Английский
Blood, Год журнала: 2022, Номер 141(13), С. 1544 - 1552
Опубликована: Дек. 1, 2022
Deleterious germ line DDX41 variants confer risk for myeloid neoplasms (MNs) and less frequently lymphoid malignancies, with autosomal dominant inheritance an estimated prevalence of 3% among MNs. Germ include truncating alleles that comprise about two-thirds all alleles, missense located preferentially within the DEAD-box domain, deletion variants. The identification a allele on tumor-based molecular profiling should prompt genetic testing because >95% such are line. Somatic mutation wild-type occurs in half MNs typically exons encoding helicase domain most as R525H. Several aspects deleterious noteworthy: (1) certain common particular populations, (2) develop at older ages typical de novo disease, challenging paradigm inherited cancer always causes disease young people, (3) despite equal frequencies these men women, progress to more frequently, suggesting gender-specific effect leukemogenesis, (4) individuals acute severe graft-versus-host after allogeneic hematopoietic cell transplantation donors than others unless they receive posttransplant cyclophosphamide, proinflammatory milieu stimulates donor-derived T cells. Biochemical studies animal models have identified DDX41's ability interact double-stranded DNA RNA:DNA hybrids roles messenger RNA splicing, ribosomal RNAs or small nucleolar processing, modulation innate immunity, disruption which could promote inflammation drive tumorigenesis.
Язык: Английский
Процитировано
40
Experimental & Molecular Medicine, Год журнала: 2023, Номер 55(11), С. 2320 - 2331
Опубликована: Ноя. 9, 2023
Abstract Nucleic acid sensing is involved in viral infections, immune response-related diseases, and therapeutics. Based on the composition of nucleic acids, sensors are defined as DNA or RNA sensors. Pathogen-associated acids recognized by membrane-bound intracellular receptors, known pattern recognition receptors (PRRs), which induce innate immune-mediated antiviral responses. PRR activation tightly regulated to eliminate infections prevent abnormal excessive an essential mechanism tumor immunotherapy gene therapies that target cancer infectious diseases through genetically engineered cells therapeutic acids. supports priming desirable responses during treatment. Recent studies have shown affects efficiency therapy inhibiting translation. Suppression immunity induced small-molecule inhibitors, virus-derived proteins, chemical modifications offers a potential strategy. Herein, we review mechanisms regulation sensing, specifically covering recent advances. Furthermore, summarize discuss research progress regarding different effects efficacy. This study provides insights for application therapy.
Язык: Английский
Процитировано
29
Blood, Год журнала: 2023, Номер 142(14), С. 1185 - 1192
Опубликована: Июль 28, 2023
Germ line variants in the DDX41 gene have been linked to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) development. However, risks associated with different remain unknown, as do basis of their leukemogenic properties, impact on steady-state hematopoiesis, links other cancers. Here, we investigate frequency significance 454 792 United Kingdom Biobank (UKB) participants identify 452 unique nonsynonymous DNA 3538 (1/129) individuals. Many were novel, prevalence most varied markedly by ancestry. Among 1059 individuals germ pathogenic (DDX41-GPV) 34 developed MDS/AML (odds ratio, 12.3 vs noncarriers). Of these, 7 218 had start-lost, 22 584 truncating, 5 257 missense ratios: 12.9, 15.1, 7.5, respectively). Using multivariate logistic regression, found significant associations DDX41-GPV MDS, AML, family history but not lymphoma, myeloproliferative neoplasms, or We also report that carriers an increased clonal hematopoiesis (CH). In fact, CH was significantly more common before sporadic DDX41-mutant MDS/AML, revealing distinct evolutionary paths. Furthermore, somatic mutation rates did differ between AML genomes, ruling out genomic instability a driver latter. Finally, higher mean red cell volume (MCV) mutations blood at risk. Collectively, our findings give new insights into cognate variants, well evolution early detection MDS/AML.
Язык: Английский
Процитировано
26
EMBO Reports, Год журнала: 2024, Номер 25(2), С. 770 - 795
Опубликована: Янв. 5, 2024
Abstract DExD/H-box helicases are crucial regulators of RNA metabolism and antiviral innate immune responses; however, their role in bacteria-induced inflammation remains unclear. Here, we report that DDX5 interacts with METTL3 METTL14 to form an m6A writing complex, which adds N6-methyladenosine transcripts toll-like receptor (TLR) 2 TLR4, promoting decay via YTHDF2-mediated degradation, resulting reduced expression TLR2/4. Upon bacterial infection, is recruited Hrd1 at the endoplasmic reticulum MyD88-dependent manner degraded by ubiquitin-proteasome pathway. This process disrupts complex halts modification as well degradation TLR2/4 mRNAs, thereby TLR2 TLR4 downstream NF-κB activation. The regulating also validated vivo, DDX5- METTL3-KO mice exhibit enhanced inflammatory cytokines. Our findings show acts a molecular switch regulate during infection shed light on mechanisms quiescent homeostasis.
Язык: Английский
Процитировано
10
Cell Death and Disease, Год журнала: 2025, Номер 16(1)
Опубликована: Янв. 31, 2025
Язык: Английский
Процитировано
1
Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)
Опубликована: Март 4, 2025
The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.
Язык: Английский
Процитировано
1
Pathogens, Год журнала: 2023, Номер 12(3), С. 437 - 437
Опубликована: Март 10, 2023
Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in trigeminal ganglion (TG). Reactivation from occurs throughout host’s life more common people with compromised immune system. causes various diseases depending on site replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, encephalitis (HSE). HSK an immunopathological condition usually consequence reactivation, anterograde transport to corneal surface, replication cells, activation innate adaptive responses cornea. recognized by cell endosomal, cytoplasmic pattern recognition receptors (PRRs) activates interferons (IFNs), chemokine cytokine production, as well recruitment inflammatory In cornea, promotes I (IFN-α/β) III (IFN-λ) IFN production. This review summarizes our current understanding PRRs IFN-mediated antiviral immunity during infection We also discuss immunopathogenesis HSK, therapeutics challenges, proposed experimental approaches, benefits promoting local IFN-λ responses.
Язык: Английский
Процитировано
15
Cell Reports, Год журнала: 2023, Номер 42(8), С. 112805 - 112805
Опубликована: Июль 18, 2023
Cellular stress in the form of disrupted transcription, loss organelle integrity, or damage to nucleic acids can elicit inflammatory responses by activating signaling cascades canonically tasked with controlling pathogen infections. These stressors must be kept check prevent unscheduled activation interferon, which contributes autoinflammation. This study examines role transcription factor myocyte enhancing 2A (MEF2A) setting threshold transcriptional R-loop accumulation. Increases R-loops lead induction interferon and a DEAD-box helicase 41 (DDX41)-, cyclic GMP-AMP synthase (cGAS)-, stimulator genes (STING)-dependent manner. The MEF2A results ATM RAD3-related (ATR) kinase, is also necessary for STING. identifies sustaining homeostasis highlights ATR positively regulating R-loop-associated responses.
Язык: Английский
Процитировано
13
Essays in Biochemistry, Год журнала: 2023, Номер 67(6), С. 905 - 918
Опубликована: Авг. 3, 2023
The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence cytosolic as a sign infection or damage. In cancer cells, this pathway can be activated through persistent damage chromosomal instability, which results in formation micronuclei exposure fragments to cytosol. from radio- chemotherapy further activate sensing responses, may occur cells themselves stromal immune tumour microenvironment (TME). cGAS-STING signalling production type I interferons, have been linked cell infiltration 'hot' tumours that are susceptible immunosurveillance immunotherapy approaches. However, recent research has highlighted complex nature signalling, with having developed mechanisms evade hijack for their own benefit. mini-review we will explore how different TME promote both anti-tumour pro-tumour responses. This includes role interferons second messenger cGAMP TME, influence on local populations. We examine alternative cascades downstream chronic interferon activation transcription factor nuclear kappa-light-chain-enhancer B (NF-κB) inflammatory cytokines, functions. An in-depth understanding contexts required harness functions signalling.
Язык: Английский
Процитировано
12
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(1), С. 652 - 652
Опубликована: Янв. 4, 2024
Due to the proliferation of genetic testing, pathogenic germline variants predisposing hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number genes. Consequently, field HHMS is gaining recognition among clinicians and scientists worldwide. Patients with abnormalities often poor outcomes are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because risk that patient may inherit variant. At present, we now face challenge incorporating these advances into clinical practice patients myelodysplastic (MDS) or acute myeloid leukemia (AML) optimizing management surveillance asymptomatic carriers, limitation evidence-based guidelines inadequate. The 2016 revision WHO classification added new section on malignant neoplasms, including MDS AML predisposition. main syndromes can classified three groups. Those without pre-existing disease organ dysfunction; DDX41, TP53, CEBPA, those platelet disorders; ANKRD26, ETV6, RUNX1, other dysfunctions; SAMD9/SAMD9L, GATA2, inherited bone marrow failure syndromes. In this review, will outline role genes involved order clarify our understanding HHMS.
Язык: Английский
Процитировано
4